3-[2-Hydroxy-4-(substituted)-phenyl]azacycloalkanes and derivatives thereof as analgesic agents and intermediates therefor

ABSTRACT

Azacycloalkanes, and derivatives thereof, including unsaturated analogs, each of which has at the 3-position a 2-hydroxy-4-substituted phenyl group wherein the 4-position substituent is alkyl which can have an oxygen atom as part of the chain, or aralkyl which can have an oxygen atom as part of the alkyl chain, their use for pharmacological and medicinal purposes, intermediates therefor and processes for their preparation.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain azacycloalkanes and derivativesthereof, including unsaturated analogs, having from 4 to 7 carbon atomsin the azacycloalkyl ring and at the 3-position a2-hydroxy-4-(Z-W-substituted)phenyl group wherein Z is alkylene havingfrom one to thirteen carbon atoms or (alk₁)_(m) --O--(alk₂)_(n) --wherein each of m and n is 0 or 1 and each of (alk₁) and (alk₂) isalkylene having from one to thirteen carbon atoms with the proviso thesummation of carbon atoms in (alk₁) plus (alk₂) is not greater thanthirteen and W is hydrogen, pyridyl, phenyl, fluorophenyl orchlorophenyl; derivatives thereof, intermediates therefor and processesfor their preparation. The products are useful as CNS agents, especiallyas analgesics, tranquilizers, sedatives and antianxiety agents inmammals, including man, and/or anticonvulsants, diuretics andantidiarrheal agents in mammals, including man.

2. Description of the Prior Art

Despite the current availability of a number of analgesic agents, thesearch for new and improved agents continues, thus pointing to the lackof an agent useful for the control of broad levels of pain andaccompanied by a minimum of side-effects. The most commonly used agent,aspirin, is of no practical value for the control of severe pain and isknown to exhibit various undesirable side-effects. Other analgesicagents such as d-propoxyphene, codeine, and morphine, possess addictiveliability. The need for improved and potent analgesic agents is,therefore, evident.

More recently, great interest in cannabinol-type compounds an analgesicagents has been exhibited. (R. Mechoulam, Ed., "Mariguana. Chemistry,Pharmacology, Metabolism and Clinical Effects", Academic Press, NewYork, N.Y., 1973; Mechoulam, et al., Chemical Reviews, 76, 75-112[1976]).

German Specification No. 2,621,535, published Nov. 25, 1976, describes3-(3,4-dihydroxyphenyl)piperidines having dopaminergic and hypotensiveactivity. Also described in this specification are intermediates to saidcompounds, including N-benzyl-, O-benzyl- or methoxy-derivatives, Δ² -and Δ³ -derivatives and3-(3,4-dibenzyloxyphenyl)-3-hydroxy-N-benzylpiperidine. N-alkyl, alkenyland aralkyl derivatives of said compounds having the same utility aredescribed in German Specification No. 2,621,536, published Nov. 25,1976.

SUMMARY OF THE INVENTION

It has now been found that certain azacycloalkanes and derivativesthereof, including unsaturated analogs, having at the 3-position a2-hydroxy-4-(substituted)phenyl group (formulae I-II below) areeffective as CNS agents, especially as analgesics, tranquilizers,sedatives and antianxiety agents in mammals, including humans, and/or asanticonvulsants, diuretics and antidiarrheal agents in mammals,including man. Also included in this invention are various derivativesof said compounds which are useful as dosage forms of the compounds,intermediates for compounds having formulae I and II, and methods fortheir preparation. The compounds have the formulae: ##STR1## (in whichstereochemistry is not represented);

wherein R₁ is selected from the group consisting of hydrogen, alkanoyhaving from one to five carbon atoms, benzyl, --P(O)(OH)₂ and the sodiumand potassium salts thereof, --CO(CH₂)₂ --COOH and the sodium andpotassium salts thereof, and --CO--(CH₂)_(p) --NR₄ R₅ wherein p is aninteger from 1 to 4, each or R₄ and R₅ when taken individually isselected from the group consisting of hydrogen and alkyl having from oneto four carbon atoms, R₄ and R₅ when taken together with the nitrogen towhich they are attached form a 5- or 6-membered heterocyclic ringselected from the group consisting of piperidino, pyrrolo, pyrrolidino,morpholino and N-alkylpiperazino having from one to four carbon atoms inthe alkyl group;

R₂ is selected from the group consisting of hydroxy and R₂ ' wherein R₂' is selected from the group consisting of hydrogen, alkyl having fromone to six carbon atoms, phenyl and phenylalkyl having from one to fourcarbon atoms in the alkyl group;

R₃ is selected from the group consisting of hydrogen and hydroxy, withthe proviso that only one of R₂ and R₃ is hydroxy;

R₆ is selected from the group consisting of hydrogen, alkenyl havingfrom two to six carbon atoms, alkynyl having from two to six carbonatoms, and R₆ ' wherein R₆ ' is selected from the group consisting ofalkyl having from one to six carbon atoms, cycloalkylmethyl having fromthree to six carbon atoms in the cycloalkyl group, phenylalkyl havingfrom one to four carbon atoms in the alkyl group, 2-furfuryl,2-tetrahydrofurfuryl, 2-thienylmethyl and 2-tetrahydrothienylmethyl;

x is 0 or an integer from 1 to 3;

Z is selected from the group consisting of (a) alkylene having from oneto thirteen carbon atoms; (b) --(alk₁)_(m) --O--(alk₂)_(n) -- whereineach of (alk₁) and (alk₂) is alkylene having from one to thirteen carbonatoms, with the proviso that the summation of carbon atoms in (alk₁)plus (alk₂) is not greater than thirteen; each of m and n is 0 or 1; and

W is selected from the group consisting of hydrogen, pyridyl, ##STR2##wherein W₁ is selected from the group consisting of hydrogen, fluoro andchloro.

Also included in this invention are the pharmaceutically acceptable acidaddition salts of those compounds of formulae I and II which contain abasic group. In compounds having two or more basic groups present, suchas those wherein the W variable is pyridyl and/or OR₁ represents a basicester moiety, polyacid addition salts are, of course, possible.Representative of such pharmaceutically acceptable acid addition saltsare the mineral acid salts such as the hydrochloride, hydrobromide,sulfate, phosphate, nitrate; organic acid salts such as the citrate,acetate, sulfosalicylate, tartrate, glycolate, malate, malonate,maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate,2-hydroxy-3-naphthoate, lactate, mandelate and methane sulfonate.

Compounds of formulae I and II contain asymmetric centers at the 3- andthe 4-positions in the azacycloalkyl moiety and may, of course, containadditional asymmetric centers in the 4-position substituent (--Z--W) ofthe benzenoid ring and in the R₆ substituent. For convenience, the aboveformulae depict the racemic compounds. However, the above formulae areconsidered to be generic to and embracive of the racemic modificationsof the compounds of this invention, the diastereomeric mixtures, thepure enantiomers and diastereomers thereof. The utility of the racemicmixture, the diastereomeric mixture as well as of the pure enantiomersand diastereomers is determined by the biological evaluation proceduresdescribed below.

In addition to the above formulae, various intermediates useful in thepreparation of compounds of formulae I and II are also included in thisinvention. The intermediates have formulae III and IV below: ##STR3##wherein R₁ ' is selected from the group consisting of hydrogen andbenzyl; and R₆ ', Z, W and x are as previously defined; and R₂ " isselected from the group consisting of hydrogen, alkyl having from one tofive carbon atoms, phenyl and phenylalkyl having from one to threecarbon atoms in the alkyl group.

Favored because of their greater biological activity relative to that ofother compounds described herein are compounds of formulae I and IIwherein R₁ is hydrogen or alkanoyl; R₂ is hydrogen or alkyl; and Z and Whave the values shown below.

    ______________________________________                                        Z                m     n     W                                                ______________________________________                                        alkylene having from 5 to 10                                                                   --    --    H                                                carbon atoms                                                                  alkylene having from 2 to 6 carbon atoms                                                       --    --                                                                                   ##STR4##                                        (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                            0     1                                                                                    ##STR5##                                        (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                            1     0                                                                                    ##STR6##                                        ______________________________________                                    

Preferred compounds of formulae I and II are those favored compounds

wherein:

each of R₁ and R₂ is hydrogen;

x = 1;

R₆ is allyl and propargyl;

Z is --C(CH₃)₂ (CH₂)₆ and W is hydrogen

or Z is --OCH(CH₃)(CH₂)₃ and W is phenyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention having formula I wherein R₃ is hydroxyare prepared from the appropriate 2-bromo 5-(Z--W substituted)phenol bya series of reactions which comprises as first step protection of thephenolic hydroxy group. Suitable protecting groups are those which donot interfere with subsequent reactions and which can be removed underconditions which do not cause undesired reactions at other sites of saidcompounds or of products produced therefrom. Representative of suchprotective groups are methyl, ethyl, benzyl or substituted benzylwherein the substituent is, for example, alkyl having from one to fourcarbon atoms, halo (Cl, Br, F, I) and alkoxy having from one to fourcarbon atoms.

The exact chemical structure of the protecting group is not critical tothis invention since its importance resides in its ability to perform inthe manner described above. The selection and identification ofappropriate protecting groups can easily and readily be made by oneskilled in the art. The suitability and effectiveness of a group as ahydroxy protecting group are determined by employing such a group in theherein-illustrated reaction sequences. It should, therefore, be a groupwhich is easily removed to regenerate the hydroxy groups. Methyl is afavored protecting group since it is easily removed by treatment withpyridine hydrochloride. The benzyl group is a preferred protecting groupsince it can be removed by catalytic hydrogenolysis or acid hydrolysis.

The protected 2-bromo-5-(Z--W substituted)phenol is then subjected tothe Grignard reaction in a reaction-inert solvent with the appropriateazacycloalkan-3-one (upper portion of Scheme A). Suitable reaction-inertsolvents are cyclic and acyclic ethers such as, for example,tetrahydrofuran, dioxane and dimethyl ether of ethylene glycol.

The Grignard reagent is formed in known manner, as, for example byrefluxing a mixture of one molar proportion of the bromo reactant andtwo molar proportions of magnesium in a reaction-inert solvent, e.g.,tetrahydrofuran. The resulting mixture is then cooled to about 0° C. to-20° C. The appropriate azacycloalkan-3-one is then added at atemperature of from about 0° C. to -20° C.

The product of the Grignard reaction (formula I, R₁ = benzyl, R₃ = OH)is then treated with an appropriate reagent to remove the protectinggroup. If desired, the benzyl group on the phenolic hydroxy group and,if present, that on the nitrogen of the azacycloalkyl moiety, areconveniently removed by catalytic hydrogenation overpalladium-on-carbon. Alternatively, the phenolic benzyl group can beremoved by acid hydrolysis using, for example, trifluoroacetic acid, ifretention of the N-benzyl group is desired. A further alternative whenretention of the N-benzyl group is desired comprises using an alkylether of the phenolic hydroxy group, preferably a methyl or ethyl etheras reactant in the Grignard reaction. Subsequent treatment of theGrignard reaction product with, for example, pyridine hydrochloride,removes the alkyl protecting group and retains the N-benzyl group.

Compounds of formula I wherein R₃ is hydroxy are dehydrated by treatmentwith a strong acid, such as hydrochloric, hydrobromic, sulfuric,hydrofluoric or p-toluenesulfonic acid to produce formula II compounds.Other dehydrating agents such as thionyl chloride, pyridine, phosphorousoxychloride, and tosyl or mesyl chloride --SO₂ plus an acid acceptorcan, of course, be used. Catalytic hydrogenation of said compounds givesformula I compounds. Of course, if either of R₁ or R₆ of the formula IIcompound is benzyl, it is removed by this catalytic hydrogenation step.

Since the compounds of this invention can have a group R₆ ' (R₆ = R₆ ')on the nitrogen of the azacycloalkyl moiety (formulae I-IV), it willfrequently not be desirable or necessary to remove the nitrogenprotecting group R₆ ' except, of course, when R₆ is to be hydrogen,alkenyl or alkynyl. The preferred nitrogen protecting group when removalof said group is necessary is benzyl since it is readily removed bycatalytic hydrogenation over palladium-on-carbon. Debenzylation isdesirably carried out on the product of the Grignard reaction to providethe corresponding 3-hydroxy-3-[4-(Z--W)-2-hydroxyphenyl]azacycloalkanewhich is subsequently dehydrated to a formula II compound wherein R₆ =R₁ = H. Catalytic hydrogenation (Pd/C) then gives a compound of formulaI. Alkylation or aralkylation of the formula I or II compound with R₆ Clor R₆ Br then provides the desired substitution on the azacycloalkylgroup. The reaction is conducted in a solvent, e.g. alkanols such asethanol, n-butanol, 1-hexanol, at a temperature of from about 50° C. tothe reflux temperature of the solvent. An acid acceptor, inorganic ororganic, is used to bind the byproduct acid formed. Suitable bases arealkali metal carbonates and hydroxides, pyridine, triethylamine,N-methylmorpholine.

A favored procedure for introducing substituents on the nitrogen of theazacycloalkyl ring is reductive alkylation (or aralkylation) using theappropriate aldehyde in the presence of a reducing agent. When theazacycloalkyl compound is of formula I, the reducing agent can bemolecular hydrogen and a catalyst, e.g. Pd/C, active metals and acids ormetal hydrides. When the azacycloalkyl compound is of formula II, i.e.an azacycloalkenyl, a metal hydride is used to avoid reducing theazacycloalkenyl group. Also, when the substituent is an alkenyl oralkynyl group, a metal hydride is used as reducing agent. Preferred asmetal reducing agent is sodium cyanoborohydride. The reaction isconducted in a reaction-inert solvent such as acetonitrile,tetrahydrofuran, alcohols having from one to four carbon atoms, ethyleneor propylene glycol, dioxane, benzene and toluene; and at a temperatureof from about 10° C. to about 50° C. The reaction is carried out atabout a neutral pH by addition of an acid such as acetic acid. ##STR7##

Appropriate azacycloalkan-3ones are those having the formula ##STR8##wherein R₆ ' is a nitrogen protecting group. The function of such agroup is to prevent undesired reactions from occurring at the nitrogenatom and which, when the desired reaction is completed, can, if desiredor necessary, be removed under conditions which do not cause undesiredreactions at other sites of the compounds or products producedtherefrom. Representative of such groups are phenylalkyl having from oneto four carbon atoms in the alkyl group, alkyl having from one to sixcarbon atoms, cycloalkylmethyl having from three to six carbon atoms inthe alkyl group, furfuryl, tetrahydrofurfuryl, 2-thienylmethyl and2-tetrahydrothienylmethyl.

The general non-availability of compounds of formula V gives rise to asituation where protection of said formula V reactant as its benzylderivative frequently affords the most convenient route to compounds offormulae I-II wherein R₆ is other than hydrogen. Debenzylation of theformulae I-II compounds wherein R₆ is benzyl and subsequent alkylationof the >NH group thereof with R₆ Cl or R₆ Br according to knownprocedures affords the desired product wherein R₆ is other than hydrogenor benzyl.

Further, since benzyl is a favored protecting group for the phenolichydroxy group, protection of both the phenolic hydroxy and the nitrogenof the azacycloalkan-3-one reactants by benzylation simplifies, byvirtue of a single reaction, regeneration of the phenolic hydroxyand >NH groups in formulae I-II compounds wherein R₆ is hydrogen.

In the lower portion of Scheme A, the 1,2,5,6-tetrahydropyridine issubjected to hydroboration and then oxidation to produce a 4-piperidinolwhich, upon oxidation by means of chromium trioxide in acetone solutionin the presence of acetic acid and sulfuric acid at a temperature offrom about -10° C. to about 20° C., affords a 4-piperidone of formulaIII.

Preparation of 4-R₂ '-substituted compounds of formulae I or II can beaccomplished in any of several ways. One method (Scheme B) comprisesreacting a compound of formula III with an appropriate Grignard reactantR₂ 'MgBr in a suitable reaction-inert solvent under conditions such asare described above to produce a 4-R₂ '-4-piperidinol which isdehydrated using an agent such as thionyl chloride-pyridine to a 4-R₂'-substituted-1,2,5,6-tetrahydropyridine. Catalytic hydrogenation thengives a saturated compound of formula I. ##STR9##

A further method comprises reacting a formula III compound with anappropriate triphenyl-R₂ "-phosphorane in dimethylsulfoxide (Scheme C).Appropriate triphenyl-R₂ "-phosphoranes are those wherein R₂ " has allvalues listed above with respect to formula IV. The 4-alkylidene oraralkylidene compound thus produced (formula IV) is then catalyticallyhydrogenated (Pd/C). Simultaneous debenzylation also occurs. ##STR10##

Acid treatment of IV causes isomerization to a compound of formula II.

a still further method, and one which is favored since it achievesintroduction of the R₂ ' substituent at an early stage, is that ofScheme D. In this scheme, a protected (R₆ ') substituted 4-piperidone isreacted with an appropriate Grignard reactant to give the corresponding4-R₂ '-4-piperidinol which is dehydrated according to the procedure ofScheme B. Hydroboration and subsequent oxidation of the protected 4-R₂'-1,2,5,6-tetrahydropyridine produces a 4-R₂ '-3-piperidinol which isthen oxidized with chromium trioxide according to the proceduredescribed above in Scheme A to give a protected 4-R₂ '-3-piperidone offormula V. Subjection of this compound to the reactions outlined inScheme A then produces compounds of formulae II and I.

Scheme D serves adequately for preparation of R₂ '-substituted productsexcept those wherein R₂ ' is benzyl. The benzyl group is convenientlyintroduced via the procedure of Scheme C. ##STR11##

The procedure described by Beckett et al., J. Med. Pharm. Chem., 1,37-58 (1959) affords a general procedure for preparation of 1-(R₆'-substituted)-4-piperidone reactants of Scheme D. The procedurecomprises reacting an appropriate amine R₆ '-NH₂ with excess ethylacrylate in a suitable solvent such as ethanol to produce thecorresponding N-di-(2-carbethoxyethyl)-R₆ '-substituted amine. Thedi-ester is then cyclized via the Dieckmann reaction using metallicsodium as base in a reaction inert solvent such as xylene to produce thecorresponding 1-R₆ '-substituted-3-carbethoxy-4-piperidone.Decarboxylation of this product is accomplished by refluxing withaqueous hydrochloric acid to produce the desired 1-R₆'-substituted-4-piperidone. The 4-piperidone thus obtained is convertedto a 3-piperidone via the method of Scheme D.

Prill et al., J. Am. Chem. Soc., 55, 1233-41 (1933), describe a generalprocedure for preparation of azacycloalkanones by which the keto groupcan, by judicious choice of reactants, be introduced at the 3- or the4-position. The procedure comprises reacting the appropriateN-substituted amino acid ethyl ester with the appropriate ethylω-bromoalkanoate to form a diester which is then cyclized by means ofsodium ethoxide to give a 1-(substituted)azacycloalkan-3(or 4)-one.

The 2-bromo-5-(Z--W substituted) phenol reactants are prepared bybromination of the appropriate 3-(Z--W substituted) phenol according tostandard procedures as, for example, by treatment with bromine in carbontetrachloride at a temperature of from about 20°-30° C. The necessary3-(Z--W substituted) phenols, if not known compounds, are prepared byprocedures illustrated herein. A convenient method for preparing suchreactants wherein the Z moiety is alkylene or (alk₁)--O--(alk₂)_(n) --comprises the Wittig reaction on an appropriate aldehyde such as2-(3-hydroxyphenyl)-2-methyl propionaldehyde, the hydroxy group of whichis protected by benzyl ether formation. The said aldehyde is thentreated with the appropriate alkyltriphenylphosphonium bromide, thealkyl group of which extends the propionaldehyde group to the desiredlength. In a typical procedure, the aldehyde reactant is added to aslurry of dimsyl sodium and alkyl triphenylphosphonium bromide indimethyl sulfoxide at a temperature below 30° C., e.g. from about 10° to30° C. When reaction is complete, the alkene substituted protectedphenol is recovered by known methods. Hydrogenation of the alkene overpalladium-on-carbon then affords the desired 3-(Z--W substituted)phenol.Judicious choice of the starting (3-hydroxyphenyl)substituted aldehydeand alkyl triphenylphosphonium bromide reactants affords the required3-(Z--W-substituted)phenol reactants.

A further procedure for making 3-(Z--W substituted) phenols wherein Z isalkylene or (alk₁)--O--(alk₂)_(n) -- comprises the Wittig reaction on anappropriate phenolic aldehyde or ketone, e.g., 3-hydroxybenzaldehyde ora (3-hydroxyphenyl)alkyl ketone, in which the phenolic hydroxy group isprotected as by conversion to the benzyl, methyl or ethyl ether. Bychoice of appropriate reactants, compounds having straight or branchedalkylene groups (Z) can be produced. When a ketone, e.g.,3-hydroxyacetophenone is used as reactant, compounds wherein Z has amethyl group on the carbon atom adjacent to the phenyl group areobtained.

Substitution of a methyl or ethyl group at other sites, e.g., theβ-carbon atom of the alkylene group, is achieved by choice of theappropriate carboalkoxy alkylidene triphenylphosphorane, e.g., (C₆ H₅)₃P═C(R')--COOC₂ H₅. The unsaturated ester thus produced is reduced to thecorresponding alcohol by reaction with lithium aluminum hydride,generally in the presence of a small amount of aluminum chloride.Alternatively, when the phenolic protecting group is other than benzyl(e.g. methyl), the alcohol is produced by catalytic reduction of theunsaturated ester using palladium-carbon, followed by treatment of thesaturated ester thus produced with lithium aluminum hydride. Conversionof the alcohol thus produced to the correponding tosylate or mesylatefollowed by alkylation of the tosylate or mesylate with an alkali metalsalt of the appropriate HO-(alk₂)-W reactant, and finally removal of theprotecting group affords the desired resorcinol 3-(Z-W substituted)phenol.

A variation of the above sequence comprises bromination of the alcoholrather than converting it to a tosylate or mesylate. Phosphoroustribromide is a convenient brominating agent. The bromo derivative isthen reacted with the appropriate HO-(alk₂)-W in the presence of asuitable base (Williamson reaction).

The bromo compounds also serve as valuable intermediates for increasingthe chain length of the alkylene moiety in the above sequence to givecompounds wherein Z is -alkylene-W. The process comprises treating thebromo derivative with triphenyl phosphine to produce the correspondingtriphenylphosphonium bromide. Reaction of the triphenylphosphoniumbromide with the appropriate aldehyde or ketone in the presence of abase such as sodium hydride or n-butyl lithium affords an unsaturatedderivative which is then catalytically hydrogenated to the correspondingsaturated compound.

An alternative method for introducing an alkyl or aralkyl group into thearomatic nucleus, and specifically such a group wherein the carbon atomadjacent the aromatic nucleus is a tertiary carbon atom, comprises acidcatalyzed electrophilic substitution of guaiacol with a tertiary alcoholin the presence of an acid, e.g. methane sulfonic acid. The generalprocedure consists in reacting a mixture of methanesulfonic acid andequimolar amounts of guaiacol and tertiary alcohol at temperatures offrom about 30° C. to about 80° C. until reaction is substantiallycomplete. The product is isolated by pouring the reaction mixture ontoice followed by extraction with a suitable solvent such as methylenechloride. The 2-methoxy-4-alkyl phenol is then converted to the desired3-alkyl phenol by removal of the phenolic hydroxy group. The processcomprises converting the hydroxy group to a dialkyl phosphate group byreaction with a dialkyl chlorophosphonate, e.g. diethylchlorophosphonate, or with diethyl phosphonate and triethylamine.Treatment of the dialkyl phosphate with lithium/ammonia followed bydemethylation of the resulting alkylated methyl ether with borontribromide or pyridine hydrochloride or other known demethylating agentsaffords the desired 3-alkylphenol.

Esters of compounds of formulae I and II wherein R₁ is alkanoyl or--CO--(CH₂)_(p) NR₄ R₅ are readily prepared by reacting formulae I andII compounds wherein R₁ is hydrogen with the appropriate alkanoic acidor acid of formula HOOC--(CH₂)_(p) --NR₄ R₅ in the presence of acondensing agent such as dicyclohexylcarbodiimide. Alternatively, theyare prepared by reaction of a formula I or II compound with theappropriate alkanoic acid chloride or anhydride, e.g., acetyl chlorideor acetic anhydride, in the presence of a base such as pyridine.

Phosphate esters are prepared by treating the appropriate 1-R₆-[3-(4-Z-W)-2-hydroxyphenyl]azacycloalkane with potassium hydridefollowed by dibenzylphosphorochloridate. Catalytic hydrogenation of thedibenzylphosphate ester affords the desired phosphate ester. Cautiousneutralization with sodium or potassium hydroxide provides thecorresponding sodium or potassium salts.

The analgesic properties of the compounds of this invention aredetermined by tests using nociceptive stimuli.

Tests Using Thermal Nociceptive Stimuli

(a) Mouse Hot Plate Analgesic Testing

The method used is modified after Woolfe and MacDonald, J. Pharmacol.Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied tothe feet of mice on a 1/8-inch thick aluminum plate. A 250 wattreflector infrared heat lamp is placed under the bottom of the aluminumplate. A thermal regulator, connected to thermistors on the platesurface, programs the heat lamp to maintain a constant temperature of57° C. Each mouse is dropped into a glass cylinder (61/2-inch diameter)resting on the hot plate, and timing is begun when the animal's feettouch the plate. The mouse is observed at 0.5 and 2 hours aftertreatment with the test compound for the first "flicking" movements ofone or both hind feet, or until 10 seconds elapse without suchmovements. Morphine has an MPE₅₀ = 4-5.6 mg./kg. (s.c.).

(b) Mouse Tail Flick Analgesic Testing

Tail flick testing in mice is modified after D'Amour and Smith, J.Pharmacol. Exp. Ther., 72, 74-79 (1941) using controlled high intensityheat applied to the tail. Each mouse is placed in a snug-fitting metalcylinder, with the tail protruding through one end. This cylinder isarranged so that the tail lies flat over a concealed heat lamp. At theonset of testing an aluminum flag over the lamp is drawn back, allowingthe light beam to pass through the slit and focus onto the end of thetail. A timer is simultaneously activated. The latency of a sudden flickof the tail is ascertained. Untreated mice usually react within 3-4seconds after exposure to the lamp. The end point for protection is 10seconds. Each mouse is tested at 0.5 and 2 hours after treatment withmorphine and the test compound. Morphine has an MPE₅₀ of 3.2-5.6 mg./kg.(s.c.).

(c) Tail Immersion Procedure

The method is a modification of the receptable procedure developed byBenbasset, et al., Arch. int. Pharmacodyn., 122, 434 (1959). Male albinomice (19-21 g.) of the Charles River CD-1 strain are weighed and markedfor identification. Five animals are normally used in each drugtreatment group with each animal serving as its own control. For generalscreening purposes, new test agents are first administered at a dose of56 mg./kg. intraperitoneally or subcutaneously, delivered in a volume of10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post drug,each animal is placed in the cylinder. Each cylinder is provided withholes to allow for adequate ventilation and is closed by a round nylonplug through which the animal's tail protrudes. The cylinder is held inan upright position and the tail is completely immersed in the constanttemperature waterbath (56° C.). The endpoint for each trial is anenergetic jerk or twitch of the tail coupled with a motor response. Insome cases, the endpoint may be less vigorous post drug. To preventundue tissue damage, the trial is terminated and the tail removed fromthe waterbath within 10 seconds. The response latency is recorded inseconds to the nearest 0.5 second. A vehicle control and a standard ofknown potency are tested concurrently with screening candidates. If theactivity of a test agent has not returned to baseline values at the2-hour testing point, response latencies are determined at 4 and 6hours. A final measurement is made at 24 hours if activity is stillobserved at the end of the test day.

Test Using Chemical Nociceptive Stimuli

Suppression of Phenylbenzoquinone Irritant-Induced Writhing

Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously ororally with saline, morphine, codeine or the test compound. Twentyminutes (if treated subcutaneously) or fifty minutes (if treated orally)later, each group is treated with intraperitoneal injection ofphenylbenzoquinone, an irritant known to produce abdominal contractions.The mice are observed for 5 minutes for the pressure or absence ofwrithing starting 5 minutes after the injection of the irritant. MPE₅₀'s of the drug pretreatments in blocking writhing are ascertained.

Tests Using Pressure Nociceptive Stimuli

Effect on the Haffner Tail Pinch Procedure

A modification of the procedure of Haffner, Experimentelle PrufungSchmerzstillender. Mittel Deutch Med. Wschr., 55, 731-732 (1929) is usedto ascertain the effects of the test compound on aggressive attackingresponses elicited by a stimulus pinching the tail. Male albino rats(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used.Prior to drug treatment, and again at 0.5, 1, 2 and 3 hours aftertreatment, a Johns Hopkins 2.5-inch "bulldog" clamp is clamped onto theroot of the rat's tail. The endpoint at each trial is clear attackingand biting behavior directed toward the offending stimulus, with thelatency for attack recorded in seconds. The clamp is removed in 30seconds if attacking has not yet occurred, and the latency of responseis recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).

Tests Using Electrical Nociceptive Stimuli

The "Flinch-Jump" Test

A modification of the flinch-jump procedure of Tenen,Psychopharmacologia, 12, 278-285 (1968) is used for determining painthresholds. Male albino rats (175-200 g.) of the Charles River(Sprague-Dawley) CD strain are used. Prior to receiving the drug, thefeet of each rat are dipped into a 20% glycerol/saline solution. Theanimals are then placed in a chamber and presented with a series of1-second shocks to the feet which are delivered in increasing intensityat 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78,1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal'sbehavior is rated for the presence of (a) flinch, (b) squeak and (c)jump or rapid forward movement at shock onset. Single upward series ofshock intensities are presented at each rat just prior to, and at 0.5,2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possibleeffect (%MPE). The %MPE of each group is statistically compared to the%MPE of the standard and the predrug control values. The %MPE iscalculated as follows: ##EQU1##

The analgesic activity of certain compounds of this invention asdetermined by the phenylbenzoquinone irritant-induced writhing (PBQ)test described above is presented below. Table I presents data forcompounds having the formula ##STR12## and Table II, for compoundshaving the formula ##STR13##

Analgesic Activity ED₅₀ (mg./kg.) or % Protection (mb./kg.)Subcutaneously

                  TABLE I:                                                        ______________________________________                                        R.sub.6       R.sub.1   R.sub.3  PBQ                                          benzyl        benzyl    OH       59(56)                                       H             H         H        49(56)*                                      H             H         H        ≧56                                   CH.sub.2 C.tbd.CH                                                                           H         H        53(10)                                       CH.sub.2 C.tbd.CH                                                                           H         H        3.78                                         TABLE II:                                                                     ______________________________________                                        R.sub.6         R.sub.1     PBQ                                               benzyl          benzyl      >56                                               benzyl          H           34.9(56)                                          H               H           32(56)*                                           CH.sub.3        H           23(56)                                            CH.sub.3        H           53(56)*                                           CH.sub.2 C.tbd.CH                                                                             H           1.65                                              CH.sub.2 C.tbd.CH                                                                             H           0.75*                                             ______________________________________                                         *HCl salt                                                                

The compounds of the present invention are active analgesics via oraland parenteral administration and are conveniently administered incomposition form. Such compositions include a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they can be administered in theform of tablets, pills, powders or granules containing such excipientsas starch, milk sugar, certain types of clay, etc. They can beadministered in capsules, in admixtures with the same or equivalentexcipients. They can also be administered in the form or oralsuspensions, solutions, emulsions, syrups and elixirs which may containflavoring and coloring agents. For oral administration of thetherapeutic agents of this invention, tablets or capsules containingfrom about 0.20 to about 100 mg. are suitable for most applications.

The physician will determine the dosage which will be most suitable foran individual patient and it will vary with the age, weight and responseof the particular patient and the route of administration. Generally,however, the initial analgesic dosage in adults may range from about 1.0to about 750 mg. per day in single or divided doses. In many instances,it is not necessary to exceed 100 mg. daily. The favored oral dosagerange is from about 1.0 to about 300 mg./day; the preferred range isfrom about 1.0 to about 50 mg./day. The favored parenteral dose is fromabout 0.1 to about 100 mg./day; the preferred range from about 0.1 toabout 20 mg./day.

This invention also provides pharmaceutical compositions, including unitdosage forms, valuable for the use of the herein described compounds asanalgesics and other utilities disclosed herein. The dosage form can begiven in single or multiple doses, as previously noted, to achieve thedaily dosage effective for a particular utility.

The compounds (drugs) described herein can be formulated foradministration in solid or liquid form for oral or parenteraladministration. Capsules containing drugs of this invention are preparedby mixing one part by weight of drug with nine parts of excipient suchas starch or milk sugar and then loading the mixture into telescopinggelatin capsules such that each capsule contains 100 parts of themixture. Tablets containing said compounds are prepared by compoundingsuitable mixtures of drug and standard ingredients used in preparingtablets, such as starch, binders and lubricants, such that each tabletcontains from 0.10 to 100 mg. of drug per tablet.

Suspensions and solutions of these drugs are frequently prepared justprior to use in order to avoid problems of stability of the drug (e.g.oxidation) or of suspensions or solution (e.g. precipitation) of thedrug upon storage. Compositions suitable for such are generally drysolid compositions which are reconstituted for injectableadministration.

Their activity as diuretic agents is determined by the procedure ofLipschitz et al., J. Pharmacol., 197, 97 (1943) which utilizes rats asthe test animals. The dosage range for this use is the same as thatnoted above with respect to the use of the herein described compounds asanalgesic agents.

Antidiarrheal utility is determined by a modification of the procedureof Neimegeers et al., Modern Pharmacology-Toxicology, Willem van Beverand Harbans Lal, Eds., 7, 68-73 (1976). Charles River CD-1 rats (170-200gms) are housed in group cages 18 hours before testing. The animals arefasted overnight with water available ad libitum prior to administrationof castor oil. The test drug is administered subcutaneously or orally ata constant volume of 5 ml./kg. of body weight in a 5% ethanol, 5%Emulphor EL-620 (a polyoxyethylated vegetable oil emulsifying agentavailable from Antara Chemicals, New York, N.Y.), and 90% saline vehiclefollowed one hour later with a challenge of castor oil (one ml.,orally). The animals are placed in small individual cages (20.5 × 16 ×21 cm.) having suspended wire floors. A disposable cardboard sheet isplaced beneath the wire floors and examined one hour after castor oilchallenge for the presence or absence of diarrhea. A vehicle/castor oiltreatment group serves as control for each day's testing. Results arerecorded as the number of animals protected at one hour post challenge.In general, the dosage levels for use of these compounds asantidiarrheal agents parallels those with respect to their use asanalgesic agents.

The tranquilizer activity of the compounds of this invention isdetermined by orally administering them to rats at doses of from about0.01 to about 50 mg./kg. of body weight and observing the subsequentdecreases in spontaneous motor activity. The daily dosage range inmammals is from about 0.01 to about 100 mg.

Anticonvulsant activity is determined by subcutaneously administeringthe test compound to male Swiss mice (Charles River) weighing 14-23 g.in a vehicle of the type used for antidiarrheal utility. The mice areused in groups of five. The day before use, the mice are fastedovernight but watered ad lib. Treatments are given at volumes of 10 ml.per kg. via a 25 gauge hypodermic needle. Subjects are treated with thetest compound and, one hour after challenge, electroconvulsive shock, 50mA. at 60 Hz. administered transcorneally. Controls are simultaneouslyrun in which the mice are given only the vehicle as control treatment.The electroconvulsive shock treatment produces tonic extensorconvulsions in all control mice with a latency of 1.5-3 seconds.Protection is recorded when a mouse exhibits no tonic extensorconvulsions for 10 seconds after administration of electroconvulsiveshock.

Antianxiety activity is determined in a manner similar to that forevaluating anticonvulsant activity except that the challenge convulsantis pentylenetetrazole, 120 mg./kg. administered intraperitoneally. Thistreatment produces clonic convulsions in less than one minute in over95% of control mice treated. Protection is recorded when the latency toconvulse is delayed at least 2-fold by a drug pretreatment.

Sedative/depressant activity is determined by treating groups of sixmice subcutaneously with various doses of test agents. At 30 and 60minutes post treatment, the mice are placed on a rotorod for one minuteand evaluated for their performance on the rotorod. Inability of themice to ride the rotorod is taken as evidence of sedative/depressantactivity.

EXAMPLE 11-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]3-hydroxypiperidine

A solution of 20.0 g. (51.4 mmols) of1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 75 ml. oftetrahydrofuran is slowly added to 2.5 g. (103 mmols) of 70-80 meshmagnesium metal. The resulting mixture is refluxed for 20 minutes and isthen cooled to -10° C. A solution of 9.71 g. (51.4 mmols) ofN-benzyl-3-piperidone in 25 ml. of tetrahydrofuran is then added at sucha rate that the reaction temperature is maintained below 0° C. Thereaction mixture is stirred for 30 minutes following completion ofaddition and is then added to 500 ml. of saturated ammonium chloride and500 ml. of ether. The ether extract is washed with two 250 ml. portionsof sodium chloride, dried over magnesium sulfate and evaporated to anoil. The oil is purified via column chromatography on 700 g. of silicagel eluted with 50% ether-cyclohexane to yield 17.1 g. (67%) of thetitle compound as an oil:

PMR: δ_(CDCl).sbsb.3 ^(TMS) 0.85 (m, terminal sidechain methyl), 1.25(s, gem dimethyl), 3.05 (m, C-2piperidine methylene), 3.10 (s, OH), 3.63(bs, N-benzyl methylene), 5.02 (s, benzyl ether methylene), 6.81 (bs,overlaps δ6.85, ArH), 6.85 (dd, J=8 and 2Hz, ArH), 7.60 (d, J=8Hz, ArH),7.25 (s, PhH) and 7.32 (s, PhH).

Ir: (chcl₃) 3448, 1618 and 1572 cm⁻¹.

Ms: m/e 499 (M⁺), 481, 408 and 390.

In like manner, the following compounds are prepared from appropriate1-bromo-2-benzyloxy-4-(Z-W)benzenes and azacycloalkan-3-ones:

    ______________________________________                                         ##STR14##                                                                     x        Z                   W                                               ______________________________________                                        0, 1, 2  CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                           H                                               0, 1     (CH.sub.2).sub.5     H                                               0, 1     CH(CH.sub. 3)(CH.sub.2).sub.2                                                                      C.sub.6 H.sub.5                                 0, 1, 2, 3                                                                             CH(CH.sub.3)(CH.sub.2).sub.3                                                                       C.sub.6 H.sub.5                                 1, 2     CH(CH.sub.3)(CH.sub.2).sub.4                                                                       4-FC.sub.6 H.sub.4                              0, 1, 3  O(CH.sub.2).sub.4    C.sub.6 H.sub.5                                 1, 2     OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      C.sub.6 H.sub.5                                 1, 2     OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      4-ClC.sub.6 H.sub.4                             0, 1     (CH.sub.2).sub.10    C.sub.6 H.sub.5                                 0, 1, 3  (CH.sub.2).sub.13    H                                               1, 3     O(CH.sub.2).sub.6    H                                               1        O(CH.sub. 2).sub.10  3-pyridyl                                       0, 1, 2  CH(CH.sub.3)(CH.sub.2).sub.3                                                                       4-pyridyl                                       1        (CH.sub.2).sub.5 O(CH.sub.2).sub.8                                                                 H                                               1, 3     CH(CH.sub.3)(CH.sub.2).sub.2 O                                                                     C.sub.6 H.sub.5                                 0, 2, 3  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                                 H                                               0, 1     O(CH.sub.2).sub.4    C.sub.6 H.sub.5                                 0, 3     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                                4-FC.sub.6 H.sub.4                              0, 2     OC(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                               4-FC.sub.6 H.sub.4                              0, 1     O(CH.sub.2).sub.5    3-pyridyl                                       1, 2     O(CH.sub.2).sub.10   4-ClC.sub.6 H.sub.4                             0, 1, 2  CH(CH.sub.3)CH.sub.2OCH.sub.2                                                                      H                                               1        CH(CH.sub.3)CH.sub.2 OCH.sub.2                                                                     C.sub.6 H.sub.5                                 0, 2     CH.sub.2 CH(CH.sub.3)O(CH.sub.2).sub.2                                                             4-FC.sub.6 H.sub.4                              ______________________________________                                    

for convenience, various values of x for given values of Z and W arecollectively tabulated.

EXAMPLE 2

3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-3-piperidinol

A mixture of 8.5 (17.03 mmols) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidine,2.0 g. of 10% palladium-on-carbon and 60 ml. of ethanol is stirred underone atmosphere of hydrogen for 2 hours. The reaction mixture is filteredthrough diatomaceous earth with ethyl acetate and evaporated. Theresidue is recrystallized from ethyl acetate to yield 3.8 g. (70%) ofthe title compound. A second crop of the title compound 0.396 g. (7%) isobtained from the mother liquor.

M.p.: 147° c.

pmr: δcdcl.sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 1.24 (s,gem dimethyl), 3.08 (bs, C-2 piperidine methylene), 6.3 (bs,exchangeable H), 6.8 (m, ArH) and 7.20 (d, J=8Hz, ArH).

Ir: (kbr) 3413, 3236 and 1613 cm⁻¹.

Ms: m/e 319 (M⁺), 301, 286, 234 and 216.

Analysis: Calc'd for C₂₀ H₃₃ NO₂ : C, 75.19; H, 10.41; N, 4.38% Found:C, 75.35; H, 10.13; N, 4.39%

In like manner, the compounds listed in Example 1 are debenzylated togive compounds having the formula below wherein x and Z-W are as definedin Example 1. ##STR15##

EXAMPLE 33-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine

A mixture of 23.6 g. (74.2 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-3-piperidinol and 400 ml. of2N hydrochloric acid is heated at reflux for 2 hours. The reaction iscooled, evaporated and dissolved in excess saturated sodium bicarbonateand 400 ml. of dichloromethane. The dichloromethane extract is combinedwith a second 400 ml. dichloromethane extract of the aqueous phase,dried over magnesium sulfate and evaporated to an oil. Crystallizationfrom ether-pentane gave 13.0 g. (58%) of the title compound.

M.P.: 122°-123° C.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.84 (m, terminal methyl), 1.10 (s, gemdimethyl), 2.50 (m, C-5 methylene), 3.32 (bt, J=6Hz, C-6 methylene),4.00 (bs, C-2 methylene), 5.90 (m, vinyl proton), 6.9 (m, ArH) and 8.42(bs, OH, NH).

Ir: (kbr) 3448, 3289, 1613 and 1575 cm⁻¹.

Ms: m/e 301 (M⁺), 286, 272, 258 and 216.

Neutralization of this compound in ether with ethanolic hydrogenchloride gives the HCl salt, M.P. 156° C. (from ether-ethanol.

Similarly, the compounds of Example 2 are dehydrated to correspondingcompounds having the formula: ##STR16##

EXAMPLE 41-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-Tetrahydropyridineand the Free Phenol

A mixture of 7.0 g. (14.0 mmols) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidineand 200 ml. of 2N hydrochloric acid is heated at reflux for 6 hours. Thereaction mixture is evaporated under reduced pressure to a thick residuewhich is dissolved in 500 ml. of saturated sodium bicarbonate-300 ml. ofether-100 ml. of dichloromethane. The organic phase is separated, driedover magnesium sulfate and evaporated to an oil. The oil is purified viacolumn chromatography on 400 g. of silica gel eluted with 50%ether-cyclohexane to yield, in order of elution, 5.1 g. (76%) of thetitle compound as an oil and 1.32 g. (24%) of1-benzyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridineas an oil.

Title Compound:

PMR: δ_(CDCl).sbsb.3^(TMS) 0.87 (m, terminal sidechain methyl), 1.28 (s,gem dimethyl), 2.48 (m, C-5 methylene of pyridine), 2.88 (m, C-6methylene of pyridine), 3.61 (bs, N-benzyl methylene), 3.82 (bs, C-2methylene of pyridine), 5.10 (s, benzyl ether methylene), 5.93 (m, vinylH), 6.8-7.3 (m, ArH) and 7.3-7.6 (m, PhH).

Ir: (chcl₃) 1653, 1610 and 1565 cm⁻¹.

Ms: m/e 481 (M⁺), 396, 390 and 91.

Phenolic Compound:

PMR: CDCl.sbsb.3^(TMS) 0.82 (m, terminal sidechain methyl), 1.22 (s, gemdimethyl), 2.40 (m, C-5 methylene of pyridine), 2.88 (t, j=6Hz, C-6methylene of pyridine), 3.42 (bs, N-benzyl methylene), 3.82 (s, C-2methylene of pyridine), 5.87 (m, vinyl H), 6.6-7.1 (m, ArH) and 7.1-7.4(m, PhH).

Ir: (chcl₃) 3509, 3175, 1667, 1623 and 1608 cm⁻¹.

Ms: m/e 391 (M⁺), 376, 306, 300, 272, 187, 120 and 91.

Similarly, the following compounds are prepared from appropriate1-bromo-2-benzyloxy-4-(Z-W)benzenes and the appropriateazacycloalkan-3-one according to the procedure of Example 1 and theabove procedure. The free phenol is also produced. (0 = phenyl)

    ______________________________________                                         ##STR17##                                                                     x*       Z                   W                                               ______________________________________                                        0, 1, 3  C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                                 H                                               1, 2     C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                                H                                               1, 2     C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                                 C.sub.6 H.sub.5                                 1        C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                                C.sub.6 H.sub.5                                 0, 1, 2  C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                                 4-pyridyl                                       0, 1     C(CH.sub.3).sub.2 (CH.sub.3).sub.3                                                                 2-pyridyl                                       1, 3     CH(CH.sub. 3)(CH.sub.2).sub.2                                                                      C.sub.6 H.sub.5                                 1, 3     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                4-ClC.sub.6 H.sub.4                             0, 1     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                                4-FC.sub.6 H.sub.4                              2        (CH.sub.2).sub.5     H                                               1, 2     OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      4-ClC.sub.6 H.sub.4                             1        (CH.sub. 2).sub.13   H                                               1        (CH.sub.2).sub.4     C.sub. 6 H.sub.5                                0, 1     (CH.sub.2).sub.8     H                                               2        (CH.sub.2).sub.3     2-pyridyl                                       1, 3     (CH.sub.2).sub.4     4-pyridyl                                       2        CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                                   3-pyridyl                                       2        CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                                   4-pyridyl                                       0, 1     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                4-pyridyl                                       0, 2     (CH.sub.2).sub.10    4-pyridyl                                       0, 1, 2, 3                                                                             OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      C.sub.6 H.sub.5                                 1, 3     O                    C.sub.6 H.sub.5                                 0, 1     O                    4-FC.sub.6 H.sub.4                              1, 2     O                    4-ClC.sub.6 H.sub.4                             1        O(CH.sub.2).sub.4    4-FC.sub.6 H.sub.4                              2        O(CH.sub.2).sub.8    C.sub.6 H.sub.5                                 2        O(CH.sub.2).sub.10   4-ClC.sub.6 H.sub.4                             0, 2     OCH(CH.sub.3)(CH.sub.2).sub.8                                                                      C.sub.6 H.sub.5                                 1        OCH(CH.sub.3)CH.sub.2                                                                              4-FC.sub.6 H.sub.4                              1        OC(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                                C.sub.6 H.sub.5                                 2        OCH.sub.2 CH(CH.sub.3)CH.sub.2                                                                     C.sub.5 H.sub.5                                 0, 3     OCH(CH.sub.3)(CH.sub.2).sub.10                                                                     H                                               2        (CH.sub.2).sub.3 O   3-pyridyl                                       1        OC(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                                H                                               1        O(CH.sub.2).sub.13   H                                               1, 2     O(CH.sub.2).sub.13   C.sub.6 H.sub.5                                 3        OCH(CH.sub.3)(CH.sub.2).sub.6                                                                      4-FC.sub.6 H.sub.4                              3        OC(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                               4-FC.sub.6 H.sub.4                              2        (CH.sub.2).sub.3 OCH(CH.sub.3)                                                                     2-pyridyl                                       1        OCH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                               4-ClC.sub.6 H.sub.4                             0        OC(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                                H                                               2        O(CH.sub.2).sub.2 C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                               H                                               0        O(CH.sub.2).sub.6    C.sub.6 H.sub.5                                 3        O(CH.sub.2).sub.12   H                                               0, 1, 3  OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      4-pyridyl                                       1        O(CH.sub.2).sub.2    4-pyridyl                                       1, 2     OCH(CH.sub.3)(CH.sub.2).sub.3                                                                      2-pyridyl                                       0        O(CH.sub.2).sub.5    3-pyridyl                                       1, 2     O                    4-pyridyl                                       0        OCH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                               4-pyridyl                                       0,1      O(CH.sub.2).sub.10   2-pyridyl                                       1        (CH.sub.2).sub.3 O(CH.sub.2).sub.3                                                                 H                                               1        CH(CH.sub.3)(CH.sub.2).sub.2 O(CH.sub.2).sub.4                                                     4-pyridyl                                       1, 2     (CH.sub.2).sub.2 O(CH.sub.2).sub.8                                                                 H                                               0, 1     (CH.sub.2).sub.6 OCH(CH.sub.3)                                                                     H                                               0        CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2 OCH(CH.sub.3)                                                  2-pyridyl                                       0, 3     (CH.sub.2  ).sub.2 O(CH.sub.2).sub.10                                                              H                                               0, 3     (CH.sub.2).sub.10 O(CH.sub.2).sub.2                                                                H                                               1, 3     C(CH.sub.3).sub.2 (CH.sub.2).sub.2 O(CH.sub.2).sub.4                                               H                                               0        (CH.sub.2).sub.4 OCH.sub.2                                                                         C.sub.6 H.sub.5                                 1        CH(CH.sub.3)(CH.sub.2).sub.2 O                                                                     C.sub.6 H.sub.5                                 1, 2     (CH.sub.2).sub.13 O  H                                               1        (CH.sub.2).sub.6 O   H                                               0        (CH.sub.2).sub.6 OCH.sub.2                                                                         4-ClC.sub.6 H.sub.4                             0        (CH.sub.2).sub.6 O   4-FC.sub.6 H.sub.4                              ______________________________________                                         *Multiple values listed under column "x" indicate preparation of compound     having the given values of Z and W.                                      

EXAMPLE 5 3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine

A mixture of 7.4 g. (24.5 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridineand 2.0 g. of 10% palladium-on-carbon in 150 ml. of ethanol and 75 ml.of ethyl acetate is stirred under one atmosphere of hydrogen for 2.5hours. The reaction is filtered through diatomaceous earth andevaporated. Crystallization of the residue from ether-pentane gave 4.6g. (62%) of the title compound.

M.P.: 138°-140° C.

PMR: δCDCl.sbsb.3 ^(TMS) 0.80 (m, terminal methyl), 1.21 (s, gemdimethyl), 6.85 (m, ArH) and 8.7 (bs, NH, OH).

MS: m/e 303 (M⁺), 288, 260, 218 and 175.

IR: (KBr) 3333 (broad), 1623 and 1592 cm⁻¹.

Neutralization of the compound in ether with ethanolic-hydrogen chloridegives the HCl salt as a hygroscopic glass after vacuum drying.

The remaining 1,2,5,6-tetrahydropyridines of Example 3 are similarlyreduced to the corresponding compounds having the formula: ##STR18##

EXAMPLE 6 3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine

A mixture of 4.2 g. (8.73 mmols) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridine,4.0 g. of 10% palladium-on-carbon and 50 ml. of ethanol is stirred underone atmosphere of hydrogen for 2 hours. The reaction mixture is filteredthrough diatomaceous earth with ethyl acetate, evaporated and theresidue again dissolved in ethyl acetate and filtered. The filtrate isevaporated and the residue crystallized in ether to yield 1.1 g. (42%)of the title compound.

The product is identical to that of Example 5.

In like manner, hydrogenation of the compounds listed in Example 3affords the corresponding compounds having the formula below wherein--Z--W and x are as defined in Example 4. ##STR19##

EXAMPLE 71-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol

To a mixture of 39.9 g. (80 mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridineand 4.8 g. (115 mmols.) of sodium borohydride in 50 ml. oftetrahydrofuran is added 21.6 ml. (180 mmols.) of borontrifluorideetherate complex in 40 ml. of tetrahydrofuran during a 2 hour period at0°-5° C. Stirring is continued 2 hours longer at 25° C. The reactionmixture is cooled in ice and quenched with 6.5 ml. of water and then 20ml. of 2N sodium hydroxide and 20 ml. of 30% hydrogen peroxide are addeddropwise. After several minutes stirring the reaction is cooled and 20ml. of concentrated hydrochloric acid is added dropwise. The reactionmixture is partially evaporated and then made basic with 6N sodiumhydroxide. The concentrated mixture is extracted with 250 ml. of ether,the ether extract washed with 100 ml. of saturated sodium chloride,dried over magnesium sulfate and evaporated. The residue is purified viacolumn chromatography on 400 g. of silica gel eluted with 50%ether-cyclohexane to yield the title compound.

Repetition of the above procedure but using the appropriate1,2,5,6-tetrahydropyridine reactants (Example 4) affords 4-piperidinolshaving the formula below wherein --Z--W and x are as defined in Example4: ##STR20##

EXAMPLE 81-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone

To a cooled solution of 24.8 g. (50 mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol, 100ml. of acetone, 6.0 g. (60 mmols.) of chromium trioxide, 15 ml. of waterand 20 ml. of acetic acid is added dropwise 20 ml. of concentratedsulfuric acid at such a rate as to maintain the temperature at 5° C. Thereaction mixture is stirred 5 hours longer (t<18° C.) and thenneutralized with concentrated ammonium hydroxide. The reaction mixtureis extracted with 500 ml. of ether, the ether extract washed once withsaturated sodium chloride, dried over magnesium sulfate and evaporated.Purification is accomplished via rapid column chromatography on 100 g.of silica gel eluted with ether to yield the title compound.

Oxidation of the 4-piperidinol compounds of Example 7 by means of theabove procedure provides corresponding 4-piperidones having the formulabelow wherein --Z--W and x are as defined in Example 7: ##STR21##

EXAMPLE 9 1-(R₆ '-substituted)-3-[2-benzyloxy-4-(Z-W)phenyl]Δ³-azacycloalkenes

The compounds tabulated below are prepared from appropriate 1-R₆'-azacycloalkan-3-ones of Preparation Y and appropriate1-bromo-2-benzyloxy-4-(Z-W)benzenes according to the procedure ofExample 4: ##STR22##

R₆ ' and x are as defined in Preparation Y and Z and W have thefollowing values:

    ______________________________________                                                  Z               W                                                   ______________________________________                                        C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                                    H                                                     CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                              H                                                     (CH.sub.2).sub.5        H                                                     (CH.sub.2).sub.13       H                                                     CH(CH.sub.3)(CH.sub.2).sub.3                                                                          C.sub.6 H.sub.5                                       CH(CH.sub.3)(CH.sub.2).sub.3                                                                          4-FC.sub.6 H.sub.4                                    CH(CH.sub.3)(CH.sub.2).sub.2                                                                          C.sub.6 H.sub.5                                       CH(CH.sub.3)(CH.sub.2).sub.2                                                                          4-ClC.sub.6 H.sub.4                                   CH(CH.sub.3)(CH.sub.2).sub.4                                                                          4-ClC.sub.6 H.sub.4                                   CH(CH.sub.3)(CH.sub.2).sub.3                                                                          4-pyridyl                                             CH(CH.sub.3)(CH.sub.2).sub.2                                                                          2-pyridyl                                             OCH(CH.sub.3)(CH.sub.2).sub.3                                                                         C.sub.6 H.sub.5                                       OCH(CH.sub.3)(CH.sub.2).sub.2                                                                         4-FC.sub.6 H.sub.4                                    OCH(CH.sub.3)(CH.sub.2).sub.3                                                                         4-pyridyl                                             O(CH.sub.2).sub.4       C.sub.6 H.sub.5                                       O(CH.sub.2).sub.4       4-pyridyl                                             O(CH.sub.2).sub.10      3-pyridyl                                             O                       4-ClC.sub.6 H.sub.4                                   O                       4-pyridyl                                             (CH.sub.2).sub.4 O      H                                                     (CH.sub.2).sub.13 O     H                                                     (CH.sub.2).sub.6 O      4-FC.sub.6 H.sub.4                                    (CH.sub.2).sub.5 O(CH.sub.2).sub.8                                                                    H                                                     (CH.sub.2).sub.4 OCH.sub.2                                                                            C.sub.6 H.sub.5                                       CH(CH.sub.3)(CH.sub.2).sub.2 O                                                                        C.sub.6 H.sub.5                                       (CH.sub.2).sub.4 O(CH.sub.2).sub.5                                                                    4-pyridyl                                             ______________________________________                                    

EXAMPLE 10 1-(R₆'-Substituted)-3-[2-benzyloxy-4-(Z-W)phenyl]-4-azacycloalkanones

The compounds of Example 7 are subjected to the procedures of Examples 7and 8 to give the following compounds wherein x, R₆ ', Z and W are asdefined in Example 9. ##STR23##

EXAMPLE 11 1-(R₆'-Substituted)-3-[2-benzyloxy-4-(Z-W)phenyl]-azacycloalkanes

Following the procedure of Example 5, the compounds of Example 7 areconverted to compounds having the formula below wherein x, R₆ ', Z and Ware as defined in Example 9. ##STR24##

EXAMPLE 121-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropylidene)piperidine

To a 15° C. solution of 4.13 g. (12.0 mmols.) of triphenyl3-phenylpropylphosphorane in 24 ml. of dimethyl sulfoxide [from 5.10 g.(12.0 mmols.) of triphenyl 3-phenylpropylphosphonium bromide and 12.0mmols. of dimsyl sodium in 24 ml. of dimethyl sulfoxide] is slowly added4.97 g. (10.0 mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10ml. of dimethyl sulfoxide. The reaction mixture is then allowed to warmto 25° C. and is then stirred at 25° C. for 4 hours. It is then added to500 ml. of ice water-250 ml. ether. The ether extract is washed with two250 ml. portions of water, dried over magnesium sulfate and evaporated.The residue is purified via column chromatography on 400 g. of silicagel eluted with 50% ethercyclohexane to yield the title compound.

Repetition of the above procedure but using the appropriate4-piperidinone compounds of Examples 8 and 10 and the appropriatetriphenyl(R₂)-phosphonium bromide reactant (C₆ H₅)₃ P⁺ R₂ '(Br)⁻ affordsthe following compounds. ##STR25## which are hydrogenated according tothe procedure of Example 5 to give compounds from Example 8 havingformula A and from Example 10, compounds having formula B: ##STR26##wherein R₆ is benzyl or R₆ ' as defined in Example 10, and x, Z and Ware as defined in Examples 8 and 10.

R₂ ' has the values:

    ______________________________________                                        C.sub.6 H.sub.5     H                                                         CH.sub.2 C.sub.6 H.sub.5                                                                          CH.sub.3                                                  (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                                  C.sub.2 H.sub.5                                           n-C.sub.5 H.sub.11  CH.sub.2 CH(CH.sub.3).sub.2                               ______________________________________                                    

The requisite triphenyl(R₂)phosphonium bromide reactants are prepared byrefluxing an equimolar mixture of triphenylphosphine and R₂ Br in asuitable solvent, e.g., acetonitrile, for from 1-2 hours. The reactionmixture is cooled and the product recovered by filtration if solid, orby evaporation of solvent if a liquid.

EXAMPLE 131-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol

To a 0° C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide in7 ml. of tetrahydrofuran is slowly added a solution of 2.48 g. (5.0mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10ml. of tetrahydrofuran. The resultant mixture is stirred for one hourand is then added to 250 ml. of saturated ammonium chloride-250 ml.ether. The ether phase is dried over magnesium sulfate and evaporated.The residue is purified via column chromatography on 200 g. of silicagel eluted with 50% ether-cyclohexane to yield the title compound.

The compounds of Examples 8 and 10 are converted to compounds tabulatedbelow by means of the above procedure and the appropriate Grignardreagent wherein x, Z and W are as defined in Examples 8 and 10. R₆ isbenzyl (Example 8 reactants) and R₆ ' (Example 10 reactants). R₂ ' hasthe values given below.

    ______________________________________                                         ##STR27##                                                                    R.sub.2 '           R.sub.2 '                                                 ______________________________________                                        CH.sub.3            n-C.sub.6 H.sub.13                                        n-C.sub.3 H.sub.7   C.sub.6 H.sub.5                                           i-C.sub.3 H.sub.7   (CH.sub.2)C.sub.6 H.sub.5                                 t-C.sub.4 H.sub.9   (CH.sub.2).sub.3 C.sub.6 H.sub.5                          ______________________________________                                    

example 141-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-1,2,5,6-tetrahydropyridine

To a -5° C. solution of 3.0 g. (4.85 mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinolin 5 ml. of pyridine is slowly added 2.89 g. (24.3 mmols.) of thionylchloride. The reaction mixture is then allowed to slowly warm to 25° C.and is stirred 12 hours longers. The reaction mixture is quenched byslow addition to 200 ml. of cold 20% potassium carbonate. The quenchedmixture is extracted with 250 ml. of ether, the extract washed once with200 ml. 20% potassium carbonate, dried over magnesium sulfate andevaporated. The residue is purified via column chromatography on 300 g.silica gel eluted with 50% ether-cyclohexane to yield the titlecompound.

In like manner, the compounds of Example 13 are dehydrated to compoundshaving the formula below wherein R₆, R₂ ' and --Z--W are as defined inExample 13. ##STR28##

Catalytic hydrogenation of the 1,2,5,6-tetrahydropyridine compounds thusproduced over Pd/C affords the corresponding compounds of the formula##STR29## wherein R₆ is hydrogen or R₆ ' as defined in Example 13,other, of course, than benzyl.

EXAMPLE 153-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol

A mixture of 6.17 g. (10.0 mmols.) of1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol,2.0 g. of 10% palladium-on-carbon and 50 ml. of ethanol is stirred underone atmosphere of hydrogen for 2 hours. The reaction mixture is filteredthrough diatomaceous earth with ethyl acetate and the filtrateevaporated. The residue is purified via crystallization fromether-pentane to yield the title compound.

Similarly, the compounds of Example 13 wherein R₆ is benzyl aredebenzylated to afford compounds having the following formula wherein R₂', Z, W and x are as defined in Example 13: ##STR30##

EXAMPLE 163-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-1,2,5,6-tetrahydropyridine

A mixture of 2.0 g. (4.57 mmols.) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol,0.95 g. (5.0 mmols.) of p-toluenesulfonic acid monohydrate and 100 ml.of toluene is heated under reflux for 2 hours with a Dean Stark trap.The reaction mixture is cooled and added to 100 ml. of 20% potassiumcarbonate-200 ml. dichloromethane. The dichloromethane extract alongwith two additional 200 ml. dichloromethane extracts of the basic phaseis dried over magnesium sulfate and evaporated. The residue iscrystallized from ether-pentane to yield the title compound.

By means of the procedure of Example 15 and the above procedure, Example13 compounds are converted to the following compounds wherein x, R₆, R₂' and --Z--W are as defined in Example 13. ##STR31##

EXAMPLE 17

The following compounds are prepared from the 1-R₆ '-4-R₂ '-piperidonesof Preparation AA and the appropriate 1-bromo-2-benzyloxy-4-(Z-W)benzeneby the procedures of Examples 1, 4 and 5. In the formula below, x, R₆ 'and R₂ ' are as defined in Preparation Z, and Z-W is one of thefollowing groups: ##STR32##

Of course, when R₆ ' in the 1-R₆ '-4-R₂ '-piperidone reactant is benzyl,it is removed in the catalytic hydrogenation step to give R₆ ' =hydrogen.

EXAMPLE 183-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-methyl-1,2,5,6-tetrahydropyridine

To a 25° C. solution of 1.0 g. (3.32 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in15 ml. of acetonitrile is added 1.32 ml. (17.6 mmoles) of 37%formaldehyde solution. After stirring for one hour the reaction iscooled to 0° C. and 332 mg. (5.3 mmole) of sodium cyanoborohydrideadded. The reaction mixture is allowed to warm to 25° C. over a one hourperiod while the pH is maintained at 7 by the addition of acetic acid.The reaction mixture is evaporated, made basic with 2N potassiumhydroxide and extracted with 200 ml. of dichloromethane. The organicextract is dried over magnesium sulfate and evaporated. The residue iscrystallized from ether-pentane to yield 350 mg. of the title compound.

M.P.: 126°-127° C.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal methyl), 1.25 (s, gemdimethyl), 2.5 (m, C-5 or C-6 methyl), 2.68 (s, N-CH₃), 2.94 (m, C-5 orC-6 methyl), 3.62 (m, C-2 methylene), 5.98 (m, vinyl proton), 6.80 (m,two ArH) and 7.05 (d, J=8Hz, ArH).

Ir: (chcl₃) 3546, 3175, 1689, 1624 and 1565 cm⁻¹.

Ms: m/e 315 (M⁺), 300, 272, 257, 230, 187.

The hydrochloride salt, prepared by neutralization of the compound inether with ethanolic hydrogen chloride, is obtained as a crystallinesolid, M.P. 179° C. (from ethanol-ether).

Analysis: Calc'd for C₂₁ H₃₃ NO.HCl: C, 71.67; H, 9.73; N, 3.98, Cl,10.07% Found: C, 71.54; H, 9.48; N, 3.94; Cl, 10.22%

By means of this procedure, the following compounds are prepared fromappropriate azacycloalkenes of Example 3 and appropriate aldehydes. Inthe formula below, x, Z and W are as defined in Example 3 and R₆ has thevalues given below. ##STR33## n-C₃ H₇ i-C₃ H₇

n-C₆ H₁₃

(ch₂)₃ c₆ h₅

(ch₂)₄ c₆ h₅

furfuryl

2-thienylmethyl

tetrahydrofurfuryl

2-tetrahydrothienylmethyl

C₃ h₅ ch₂

c₄ h₇ ch₂

c₆ h₁₁ ch₂

c₅ h₉ ch₂

hydrogenation of these compounds according to the procedure of Example 2but using 5% palladium-on-carbon in place of 10% palladium-on-carbonaffords the corresponding saturated compounds.

EXAMPLE 193-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-methylpiperidine

A mixture of 600 mg. (1.98 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-piperidine, 0.78 ml. of 37%formaldehyde, 1.98 ml. of 1N hydrochloric acid and 150 mg. of 5%palladium-on-carbon is hydrogenated under 55 p.s.i. of hydrogen for 1.5hours. The reaction mixture is filtered through diatomaceous earth andconcentrated under reduced pressure. The residue is diluted with 75 ml.of saturated sodium bicarbonate and extracted with two 75 ml. portionsof dichloromethane. The combined extract is washed with 75 ml. ofsaturated sodium chloride, dried over magnesium sulfate and evaporatedto yield 567 mg. (90%) of the title compound as an oil.

PMR: δ_(CDCl) ₃.sbsb.3^(TMS) 0.80 (m, terminal methyl), 1.25 (s, gemdimethyl), 2.37 (s, N-methyl), 3.05 (m) and 6.75 (m, ArH).

Ir: (chcl₃) 3390, 1629 and 1575 cm⁻¹.

Ms: m/e 317 (M⁺), 302 and 233.

Neutralization of the compound in ether with ethanolic hydrogen chloridegives the hydrochloride salt, M.P. 198°-199° C. (from ether-ethanol).

Reductive alkylation of compounds of Example 6 according to the aboveprocedure but using the appropriate aldehyde affords the followingcompounds wherein x, Z and W are as defined in Example 6:

    ______________________________________                                         ##STR34##                                                                    R.sub.6             R.sub.6                                                   ______________________________________                                        C.sub.2 H.sub.5     2-thienylmethyl                                           i-C.sub.4 H.sub.9   C.sub.3 H.sub.5 CH.sub.2                                  n-C.sub.6 H.sub.13  C.sub.5 H.sub.9 CH.sub.2                                  (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                                  furfuryl                                                  ______________________________________                                    

EXAMPLE 203-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-(2-propynyl)piperidine

A mixture of 0.900 g. (2.97 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine, 481 mg. (3.49mmoles) of anhydrous potassium carbonate and 353 mg. (2.97 mmoles) of1-bromo-2-propyne in 20 ml. of ethanol is heated at reflux for 22 hours.The reaction mixture is then evaporated and dissolved in 100 ml. ofsaturated sodium bicarbonate and 200 ml. of dichloromethane. The organicextract is washed with two 150 ml. portions of saturated sodiumchloride, dried over magnesium sulfate and evaporated. The residue ispurified via column chromatography on 100 g. silica gel eluted with 2%methanol-dichloromethane. The product is crystallized from pentane (117mg., 11.5%).

M.P.: 91°-93° C.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.82 (m, terminal methyl), 1.22 (s, gemdimethyl), 2.41 (t, J=2Hz, acetylenic methine), 3.57 (d, J=2Hz,acetylenic methylene) and 6.85 (m, ArH).

Ir: (chcl₃) 3356, 1637 and 1582 cm⁻¹.

Ms: m/e 341 (M⁺), 326, 257 and 256.

Neutralization of the product in ether with ethanolic hydrogen chloridegives the HCl salt, M.P. 180°-181° C. (from ethanol-ether).

Similarly, the azacycloalkanes of Example 6 are alkylated to give thefollowing compounds wherein x, Z and W are as defined in Example 6 andR₆ is:

    __________________________________________________________________________     ##STR35##                                                                    R.sub.6     R.sub.6       R.sub.6                                             __________________________________________________________________________    CH.sub.2CH  CH(C.sub.3 H.sub.7)CCH                                                                      (CH.sub.2).sub.2CCH                                 (CH.sub.2).sub.3CCH                                                                       CC(CH.sub.2).sub.3 CH.sub.3                                                                 CCH                                                 (CH.sub.2).sub.2 CCCH.sub.3                                                               CH.sub.2CC(CH.sub.2).sub.2 CH.sub.3                                                         C(CH.sub.3) (C.sub.2 H.sub.5)C CH                   __________________________________________________________________________

example 213-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1-N-(2-propynyl)-1,2,5,6-tetrahydropyridine

A mixture of 1.0 g. (3.33 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine,539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 395 mg. (3.32mmoles) of 1-bromo-2-propyne in 23 ml. of ethanol is heated at refluxfor 20 hours. The reaction mixture is evaporated and dissolved in 100ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. Theorganic extract is washed with two 150 ml. portions of saturated sodiumchloride, dried over magnesium sulfate and evaporated. The residue iscrystallized from pentane to yield 161 mg. of the title compound.

M.P.: 116°-117° C.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.86 (m, terminal methyl), 1.24 (s, gemdimethyl), 2.23 (t, J=2Hz, acetylenic methine), 2.45 (m, C-5 methylene),2.78 (t, J=6Hz, C-6 methylene), 3.33 (m, C-2 methylene), 3.48 (d, J=2Hz,acetylenic methylene), 5.93 (m, vinyl proton), 6.9 (m, two ArH), and7.05 (d, J=8Hz, ArH).

Ir: (chcl₃) 3571, 3333, 1637 and 1572 cm⁻¹.

Ms: m/e 339 (M⁺), 324, 300, 254 and 187.

Neutralization of the compound in ether with ethanolic hydrogen chloridegives the hydrochloride salt, M.P. 158° C. (from ether-ethanol).

Analysis: Calc'd for C₂₃ H₃₃ NO.HCl: C, 73.48; H, 9.12; N, 3.72% Found:C, 73.37; H, 8.91; N, 3.73%

The following compounds are prepared in like manner by the aboveprocedure from appropriate alkynyl bromides and compounds of Example 3:##STR36## wherein x, Z and W are as defined in Example 3 and R₆ is:

    ______________________________________                                        CH.sub.2 C.tbd.CH                                                                       (CH.sub.2).sub.4 C.tbd.CH                                                                    (CH.sub.2).sub.3 --C.tbd.C--CH.sub.3                 (CH.sub.2).sub.2 C.tbd.CH                                                               CH(C.sub.3 H.sub.7)--C.tbd.CH                                                                C.tbd.CH                                             ______________________________________                                    

EXAMPLE 223-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-(2-propenyl)piperidine

A mixture of 900 mg. (2.97 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine, 481 mg. (3.48mmoles) of anhydrous potassium carbonate and 359 mg. (2.97 mmoles) ofallyl bromide in 20 ml. of ethanol is heated at reflux for 23 hours. Thereaction mixture is concentrated under reduced pressure and the residuedissolved in 250 ml. of saturated sodium bicarbonate and 200 ml. ofdichloromethane. The organic extract is washed once with 100 ml. ofsaturated sodium chloride, dried over magnesium sulfate and evaporatedunder reduced pressure to an oil. The oil is purified via columnchromatography on 125 g. of silica gel eluted with 25% cyclohexane-etherto yield 172 mg. (15%) of3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-piperidineas an oil and 411 mg. (40%) of the title compound as an oil. TitleCompound: PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal methyl), 1.25 (s,gem dimethyl), 3.1 (m, allyl methylene and C-2 or 6 methylene), 5.0-5.4and 5.5-6.1 (m, three vinyl protons) and 6.8 (m, ArH).

Ir: (chcl₃) 1681, 1653, 1626 and 1597 cm⁻¹.

Ms: m/e 343 (M⁺), 328, 316, 302, 259 and 258 cm⁻¹.

Neutralization of the title compound with ethanolic hydrogen chloridegives the hydrochloride salt as a glass. Bis Allyl Compound: PMR:δ_(CDCl).sbsb.3^(TMS) 0.80 (m, terminal methyl), 1.22 (s, gem dimethyl),2.98 and 3.10 (bs, allyl methylenes), 4.09 (dd, J=8 and 6Hz, one H ofC-2 methylene), 4.50 (dd, J=16 and 8Hz, one H of C-2 methylene), 4.9-5.4and 5.5-6.1 (m, six vinyl protons), 6.69 (d, J=2Hz, ArH), 6.71 (dd, J=8and 2Hz, ArH) and 7.00 (d, J=8Hz, ArH).

Ir: (chcl₃) 3521, 3226, 1653, 1629 and 1565 cm⁻¹.

Ms: m/e 383 (M⁺), 368, 342, 298 and 257.

EXAMPLE 233-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-(2-propenyl)-1,2,5,6-tetrahydropyridine

A mixture of 1.0 g. (3.32 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine,539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 401 mg. (3.32mmoles) of allyl bromide in 23 ml. of ethanol is heated at reflux for 23hours. The reaction mixture is concentrated under reduced pressure andthe residue dissolved in 250 ml. of saturated sodium bicarbonate and 200ml. of dichloromethane. The organic extract is washed once with 100 ml.of saturated sodium chloride, dried over magnesium sulfate andevaporated to an oil. The oil is purified via column chromatography on125 g. of silica gel eluted with 5% methanol-dichloromethane to yield372 mg. (29%) of3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-1,2,5,6-tetrahydropyridineas an oil and 247 mg. (22%) of the title compound, M.P. 109°-110° C.(from ether-pentane). Title Compound: PMR: α_(CDCl).sbsb.3^(TMS) 0.85(m, terminal methyl), 1.25 (s, gem dimethyl), 3.23 (m, allyl methylene),5.0-5.4 and 5.5-6.1 (m, four vinyl protons), 6.82 (m, ArH) and 6.97 (d,J=8Hz, ArH).

Ir: (chcl₃) 3425, 1631 and 1572 cm⁻¹.

Ms: m/e 341 (M⁺), 326, 300, 272 and 256.

Neutralization of the title compound with ethanolic hydrogen chloridegives the hydrogen chloride salt as a glass. Bis Allyl Compound: PMR:α_(CDCl).sbsb.3^(TMS) 0.82 (terminal methyl), 1.25 (s, gem dimethyl),3.03 and 3.12 (two m, allyl methylenes), 3.9-5.4 and 5.5-6.1 (m, sevenvinyl protons), 6.71 (d, J=2Hz, ArH), 6.72 (dd, J=8 and 2Hz, ArH) and7.13 (d, J=8Hz, ArH).

Ir: (chcl₃) 3521, 3215, 1653, 1629 and 1565 cm⁻¹.

Ms: m/e 381 (M⁺), 366, 340, 312, 284, 271 and 260.

EXAMPLE 241-N-Cyclopropylmethyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine

To a solution of 596 mg. (1.98 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in2.25 ml. of toluene and 4.5 ml. of pyridine is added 180 μl (3.96mmoles) of cyclopropanecarboxylic acid chloride in 2.25 ml. of toluene.The reaction mixture is stirred for one hour at 25° C. and for 0.5 hourat 80° C. Another 180 μl (3.96 mmoles) portion of cyclopropanecarboxylicacid chloride is added and the heating at 80° C. continued for 2 hours.The reaction mixture is cooled and added to 300 ml. of saturated sodiumchloride. The quenched mixture is extracted with two 75 ml. portions ofdichloromethane. The extract is washed once with 50 ml. of saturatedsodium chloride, dried over magnesium sulfate and evaporated to yield anoil. A solution of this oil in 100 ml. of ether is added dropwise to amixture of 3.0 g. (78.9 mmoles) of lithium aluminum hydride in 150 ml.of ether. The reaction mixture is refluxed for 17 hours, cooled in iceand decomposed by the addition of 3 ml. of water, 3 ml. of 15% sodiumhydroxide and 9 ml. more of water. After stirring for 30 minutes at 25°C. the quenched reaction mixture is filtered and the filtrate evaporatedto a solid. Recrystallization from dichloromethane and pentane gives 296mg. (42%) of the title compound.

Mp: 118° c.

pmr: α_(cdcl).sbsb.3^(TMS) 0.2 and 0.5 (m, cyclopropane), 0.84 (m,terminal methyl), 1.28 (s, gem dimethyl), 2.40 (m, C-5 or 6 and C-1methylene), 2.75 (t, J=6Hz, C-5 or 6 methylene), 3.26 (m, C-2methylene), 5.80 (m, vinyl H), 6.75 (m, two ArH) and 6.96 (d, J=8Hz,ArH).

Ms: m/e 355 (M⁺), 340, 314, 300 and 270.

Neutralization of the title compound in ether with ethanolic hydrogenchloride gives the hydrochloride salt of the title compound as a foam.

In a similar manner the following compounds were prepared:

1-N-Cyclopropylmethyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-piperidineas an oil (515 mg., 73%) from3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine (600 mg., 1.98mmoles) and cyclopropane carboxylic acid chloride (360 μl, 7.82 mmoles).

PMR: α_(CDCl).sbsb.3^(TMS) 0.25 and 0.55 (m, cyclopropane), 0.82(terminal methyl), 1.25 (s, gem dimethyl), 2.39 (d, J=6Hz, C-1methylene), 6.61 (dd, J=8 and 2Hz, ArH), 6.79 (d, J=2Hz, ArH) and 6.95(d, J=8Hz, ArH).

Ir: (chcl₃) 1639 and 1580 cm⁻¹.

Ms: m/e 357, 342, 316, 302 and 273.

Neutralization of the title compound in ether with ethanolic hydrogenchloride gives the hydrochloride salt of the title compound as a foam.

1-N-Cyclobutylmethyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine(198 mg., 39%) from3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine(412 mg., 1.37 (mmoles) and cyclobutane carboxylic acid chloride (586μl, 5.48 mmoles).

MP: 116°-117° C. (from dichloromethane-pentane).

PMR: α_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal methyl), 1.25 (s, gemdimethyl), 2.40 and 2.80 (m, C-5, 6 and 1 methylenes), 3.48 (bs, C-2methylene), 5.90 (m, vinyl H), 6.82 (m, ArH) and 7.02 (d, J=8Hz, ArH).

Ir: (chcl₃) 3571, 3279, 1634 and 1572 cm⁻¹.

Ms: m/e 369 (M⁺), 354, 314, 300 and 284.

Neutralization of the title compound in ether with ethanolic hydrogenchloride affords the hydrochloride salt of the title compound as a foam.

1-N-Cyclobutylmethyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidineas an oil (427 mg., 86%) from3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine (415 mg., 1.37mmoles) and cyclobutanecarboxylic acid chloride (586 μl, 5.48 mmoles).

PMR: α_(CDCl).sbsb.3^(TMS) 0.82 (m, terminal methyl), 1.25 (s, gemdimethyl), 6.60 (dd, J=8 and 2Hz, ArH), 6.76 (d, J=2Hz, ArH) and 6.82(d, J=8Hz, ArH).

Ir: (chcl₃) 1637 and 1575 cm⁻¹.

Ms: m/e 371 (M⁺), 356, 316 and 302.

Neutralization of the title compound in ether with ethanolic hydrogenchloride, produces the hydrochloride salt of the title compound as afoam.

EXAMPLE 25 1-Acetyl-3-[2-acetoxy-4-(1,1-dimethylheptyl)phenyl]piperidine

To a solution of 2.0 g. of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine in 20 ml. ofpyridine at 10° C. is added 20 ml. of acetic anhydride and the mixturestirred under nitrogen for 18 hours. It is then poured onto ice/waterand acidified with dilute hydrochloric acid. The product is isolated byextraction with ethyl acetate (2 × 100 ml.). The combined extracts arewashed with brine, dried (MgSO₄) and evaporated to give the product asan oil.

In like manner, the compounds of formulae I and II wherein R₆ ishydrogen and R₁ is hydrogen are converted to their diacyl derivatives.Replacement of acetic anhydride by propionic, butyric or valeric acidanhydrides affords the corresponding diacyl derivatives.

When R₆ is other than hydrogen, the above procedure produces themonoacyl derivative of the phenolic hydroxy group.

EXAMPLE 263-[2-(4-Morpholinobutyryloxy)-4-(1,1-dimethylheptyl)phenyl]piperidine

Dicyclohexylcarbodiimide (0.227 g., 1.1 mmole) and 4-N-piperidylbutyricacid hydrochloride (0.222 g., 1.0 mmole) are added to a solution of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine (0.303 g., 1.0mmole) in methylene chloride (25 ml.) at room temperature. The mixtureis stirred for 18 hours and is then cooled to 0° C. and filtered.Evaporation of the filtrate affords the title product as itshydrochloride salt.

Similarly, the reactant of this example and the remaining phenoliccompounds of this invention are converted to the basic esters of thephenolic hydroxy group by reaction with the appropriate basic acidreagent. Esters wherein the R₁ moiety has the following values are thusprepared:

--COCH₂ NH₂

--co(ch₂)₂ n(c₄ h₉)₂

--co(ch₂)₂ -n-(methyl)piperazino

--COC(CH₃)₂ (CH₂)₂ -piperidino

--CO(CH₂)₃ N(C₂ H₅)₂

--coch(ch₃)(ch₂)₂ -morpholino

--CO(CH₂)₃ -pyrrolo

--CO(CH₂)₃ -pyrrolidino

--COCH₂ -pyrrolo

--CO(CH₂)₃ -piperidino

--CO(CH₂)₄ NH₂

--co(ch₂)₃ nh(c₃ h₇)

--co(ch₂)₂ -n-butylpiperazino

Careful neutralization of the hydrochloride salts affords the free basicesters which are converted to other acid addition salts according to theprocedure of Example 18. In this manner, the hydrobromide, sulfate,acetate, malonate, citrate, glycolate, gluconate, succinate,sulfosalicylate and tartrate salts are prepared.

EXAMPLE 27 General Hydrochloride Salt Formation

Excess hydrogen chloride is passed into a solution of the appropriatecompound of formulae I-II and the resulting precipitate separated andrecrystallized from an appropriate solvent, e.g. methanol-ether (1:10).

The remaining compounds of formulae I-II are converted to theirhydrochlorides in like manner.

Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate,butyrate, citrate, malonate, maleate, fumarate, malate, glycolate,gluconate, lactate, salicylate, sulfosalicylate, succinate, pamoate,tartrate and embonate salts are prepared.

EXAMPLE 28 3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine2'-O-hemisuccinate Ester Sodium Salt

To a 0° C. solution of 0.606 g. (2.0 mmoles) of3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine in 3 ml. ofdichloromethane is added 0.244 g. (2.0 mmoles) of4-N,N-dimethylaminopyridine. To the resultant solution is slowly added0.200 g. (2.0 mmoles) of succinic anhydride in one ml. ofdichloromethane. The reaction mixture is stirred for 4 hours at 0° C.and then 2.00 ml. of 1N hydrochloric acid is slowly added. The reactionmixture is stirred 5 minutes longer and then added to 100 ml. water-100ml. dichloromethane. The dichloromethane extract is dried over magnesiumsulfate and evaporated. The residue is dissolved in 5 ml. of ethanol and2.00 ml. of 1N sodium hydroxide in ethanol added. Addition of ethercauses crystallization. Recrystallization from ethanol-ether yields thetitle compound.

Replacement of sodium hydroxide by potassium hydroxide in the aboveprocedure affords the potassium salt.

By means of this procedure, the remaining compounds described herein areconverted to their hemisuccinate esters.

EXAMPLE 29 3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine2'-O-Phosphate Ester Monosodium Salt

To a 0° C. slurry of 0.126 g. (3.14 mmoles) of potassium hydride in 3ml. of dimethylformamide is added a solution of 0.953 g. (3.14 mmoles)of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine in 3 ml. ofdimethylformamide. After gas evolution ceases (˜10 min.) 0.932 g. (3.14mmoles) of dibenzylphosphochlridate is slowly added. The reactionmixture is stirred for one hour and then added to 200 ml. ether-100 ml.water. The ether extract is washed with two 100 ml. portions of water,dried over magnesium sulfate and evaporated to a residue. The residue ismixed with 1.0 g. of 5% platinum on carbon and 25 ml. of ethanol andstirred under one atmosphere of hydrogen for 3 hours. The reactionmixture is filtered through diatomaceous earth and 3.14 ml. of 1N sodiumhydroxide in ethanol slowly added to the filtrate. Addition of ethercauses crystallization of the product. Recrystallization from ethanolthen yields the title compound.

Similarly, the remaining compounds described herein are converted totheir phosphate ester monosodium salts and, by replacement of sodiumhydroxide with potassium hydroxide, to their corresponding potassiumsalts.

EXAMPLE 30

One hundred mg. of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidineare intimately mixed and ground with 900 mg. of starch. The mixture isthen loaded into telescoping gelatin capsules such that each capsulecontains 10 mg. of drug and 90 mg. of starch.

EXAMPLE 31

A tablet base is prepared by blending the ingredients listed below:

    ______________________________________                                         Sucrose         80.3 parts                                                   Tapioca starch   13.2 parts                                                   Magnesium stearate                                                                              6.5 parts                                                   ______________________________________                                    

Sufficient1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridineis blended into this base to provide tablets containing 0.1, 0.5, 1, 5,10 and 25 mg. of drug.

EXAMPLE 32

Suspensions of1-benzyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridineare prepared by adding sufficient amounts of drug to 0.5%methylcellulose to provide suspensions having 0.05, 0.1, 0.5, 1, 5 and10 mg. of drug per ml.

PREPARATION A 2-(3-Benzyloxyphenyl)-2-methylpropionitrile

To a solution of 1500 ml. of dimethylsulfoxide saturated with methylbromide is simultaneously added a solution of 294 g. (1.32 mole) of2-(3-benzyloxyphenyl)acetonitrile in 200 ml. dimethyl sulfoxide and asolution of 420 ml. of 50% aqueous sodium hydroxide. Methyl bromide iscontinuously bubbled through the reaction mixture during the aboveaddition (30 minutes) and then for 1.5 hours longer while the reactiontemperature is maintained at ≦50° C. with ice cooling. The reactionmixture is added to 2 liters of water-2 kg. ice and the resultantmixture extracted four times with 1 liter of ether. The combined etherextracts are washed twice with one liter of water, once with one literof saturated sodium chloride, dried over magnesium sulfate andevaporated to yield 325 g. (98%) of product as an oil.

PMR: α_(CDCl).sbsb.3^(TMS) 1.70 (s, methyl), 5.12 (s, methylene),6.8-7.5 (m, ArH) and 7.45 (s, PhH).

Ir: (chcl₃) 2247, 1616 and 1603 cm⁻¹.

Ms: m/e 251 (M⁺), 236, 160 and 91.

PREPARATION B 2-(3-Benzyloxyphenyl)-2-methylpropionaldehyde

To a 15° C. solution of 325 g. (1.25 mole) of2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters oftetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a1.3 M solution in hexane (reaction temperature is maintained at 15°-18°C.). The reaction mixture is allowed to warm to room temperature and isstirred 2 hours longer. It is then quenched by addition to a solution of170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature≦30° C.). The resultant mixture is allowed to warm to room temperatureand is then stirred an additional 2 hours. The organic layer isseparated and the aqueous phase extracted once with one liter of ether.The combined organic phase is washed with 500 ml. of water and 500 ml.of saturated sodium chloride, dried over magnesium sulfate andevaporated to yield 315 g. (99%) of the title product.

PMR: α_(CDCl).sbsb.3^(TMS) 1.43 (s, methyls), 5.08 (s, methylenes),6.8-7.5 (m, ArH), 7.4 (s, PhH) and 9.55 (s, aldehyde).

PREPARATION C 2-(3-Benzyloxyphenyl)-2-methyl-cis-oct-3-ene

To a 15° C. solution of 1.8 moles of dimsyl sodium (from sodium hydrideand dimethyl sulfoxide) in 2 liters of dimethyl sulfoxide is added,portionwise, 768 g. (1.8 moles) of pentyltriphenylphosphonium bromide.The resultant slurry is stirred 15 minutes at 15°-20° C. and then 3.5 g.(1.24 moles) of 2-(3-benzyloxyphenyl)-2-methylpropionaldehyde is slowlyadded (reaction temperature ≦30° C.). The resultant mixture is stirredfor 4 hours at room temperature and is then added to 6 liters of icewater. The quenched reaction is extracted four times with one literportions of 50% ether-pentane. The combined extract is washed twice withone liter of water and once with one liter of saturated sodium chlorideand is then dried over magnesium sulfate and evaporated to yield an oil.Crystallization of this oil in 50% ether-pentane (to removetriphenylphosphine oxide), filtration and evaporation of the filtrategives 559 g. of oil. The crude oil is purified via column chromatographyon 2 kg. of silica gel eluted with 20% hexane-dichloromethane to yield217 g. (57%) of 2-(3-benzyloxyphenyl)-2-methyl-cis-oct-3-ene.

PMR: α_(CDCl).sbsb.3^(TMS) 0.75 (bt, J=6Hz, terminal methyl), 1.1 (m,two sidechain methylenes), 1.43 (s, gem dimethyl), 1.60 (m, allylic r 4hours at room temperature and is then added to 6 liters of ice water.The quenched reaction is extracted four times with one liter portions of50% ether-pentane. The combined extract is washed twice with one literof water and once with one liter of saturated sodium chloride and isthen dried over magnesium sulfate and evaporated to yield an oil.Crystallization of this oil in 50% ether-pentane (to removetriphenylphosphine oxide), filtration and evaporation of the filtrategives 559 g. of oil. The crude oil is purified via column chromatographyon 2 kg. of silica gel eluted with 20% hexane-dichloromethane to yield217 g. (57%) of 2-(3-benzyloxyphenyl)-2-methyl-cis-oct-3-ene.

PMR: α_(CDCl).sbsb.3^(TMS) 0.75 (bt, J=6Hz, terminal methyl), 1.1 (m,two sidechain methylenes), 1.43 (s, gem dimethyl), 1.60 (m, allylicmethylene), 5.09 (s, benzylic methylene), 5.28 (dt, J=12 and 6Hz, vinylH), 5.70 (dd, J=12 and 1Hz, vinyl H), 6.7-7.5 (m, ArH) and 7.42 (s,PhH).

Ir: (chcl₃) 1610 and 1587 cm⁻¹.

Ms: m/e 308 (M⁺), 293, 274, 265, 251, 239, 225, 217 and 91.

Similarly, 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g., 70%)is prepared from 15.75 g. (0.062 mol.) of2-(3-benzyloxyphenyl)-2-methylpropionaldehyde and 37.5 g. (0.0899 mol.)of hexyltriphenylphosphonium bromide. The product is an oil.

PMR: α_(CDCl).sbsb.3^(TMS) 0.78 (m, terminal sidechain methyl), 1.40 (s,gem dimethyl), 4.97 (s, benzyl ether methylene), 5.23 (m, vinyl H), 5.57(d, J=11 Hz, vinyl H) and 6.6-7.4 (m, ArH and PhH).

Ir: (chcl₃) 1608 and 1582 cm⁻¹.

Ms: m/e 322 (M⁺), 307, 279, 274, 265 and 231.

PREPARATION D 2-(3-Hydroxyphenyl)-2-methyloctane

A mixture of 65 g. (0.211 mole) of2-(3-benzyloxyphenyl)-2-methylcis-oct-3-ene and 7.5 g. of 10%palladium-on-carbon in 100 ml. of ethanol is hydrogenated for one houron a Parr apparatus at 50 p.s.i. hydrogen pressure. Additional 7.5 g.portions of 10% palladium-on-carbon are added after one and two hours ofreaction and the reaction continued for 12 more hours. The reactionmixture is filtered through diatomaceous earth with ethanol and thefiltrate evaporated to an oil. The oil is purified via columnchromatography on one kg. of silica gel eluted with 50%hexane-dichloromethane to yield 105g. (78%) of2-(3-hydroxyphenyl)-2-methyloctane.

PMR: α_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 1-1.9 (m,methylenes), 1.29 (s, gem dimethyl), 4.98 (s, phenol H) and 6.6-7.4 (m,ArH).

Ir: (chcl₃) 3571, 3311 and 1592 cm⁻¹.

Ms: m/e 220 (M⁺), 205 and 135.

In like manner, 2-(3-hydroxyphenyl)-2-methylnonane is prepared in 82%(7.8 g.) yield from 13.0 g. (0.0406 mol.) of1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene. It is obtained as an oilhaving the characteristics:

PMR: α_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal methyl), 1.27 (s, gemdimethyl), 5.25 (bs, OH) and 6.6-7.4 (m, ArH).

Ir: (chcl₃) 3571, 3279, 1563 and 1527 cm⁻¹.

Ms: m/e 234 (M⁺), 219, 191, 178, 164, 149, 135 and 121.

PREPARATION E 2-(4-Bromo-3-hydroxyphenyl)-2-methyloctane

To a 0° C. solution of 110 g. (0.50 mole) of2-(3-hydroxyphenyl)-2-methyloctane in 200 ml. of carbon tetrachloride isadded dropwise a solution of 80 g. (0.50 mole) of bromine in 90 ml. ofcarbon tetrachloride (reaction temperature ≦30° C. with cooling). Thereaction mixture is stirred an additional 15 minutes and is thenevaporated to yield 150 g. (100%) of2-(4-bromo-3-hydroxyphenyl)-2-methyloctane.

PMR: α_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 0.8-1.9 (m,methylenes), 1.28 (s, gem dimethyl), 5.4 (bs, phenolic H), 6.78 (dd, J=8and 2Hz, C-6 ArH), 7.02 (d, J=2Hz, C-2 ArH) and 7.37 (d, J=8Hz, C-5ArH).

In like manner, 2-(4-bromo-3-hydroxyphenyl)-2-methylnonane is preparedin 82% (8.5 g.) yield as an oil from 7.8 g. (0.033 mol.) of2-(3-hydroxyphenyl)-2-methylnonane:

PMR: α_(CDCl).sbsb.3^(TMS) 0.86 (m, terminal methyl), 1.27 (s, gemdimethyl), 5.50 (bs, OH), 6.83 (dd, J=8 and 2Hz, ArH), 7.08 (d, J=2Hz,ArH) and 7.43 (d, J=8 Hz, ArH).

Ir: (chcl₃) 3279, 1613 and 1587 cm⁻¹.

Ms: m/e 314, 312 (M⁺), 212, 210, 185 and 187.

PREPARATION F 2-(3-Benzyloxy-4-bromophenyl)-2-methyloctane

To a -18° C. slurry of 23.0 g. (0.575 mole) of potassium hydride in 400ml. of N,N-dimethylformamide is added over a 45 minute period a solutionof 150 g. (0.5 mole) of 2-(4-bromo-3-hydroxyphenyl)-2-methyloctane in400 ml. of N,N-dimethylformamide (reaction temperature ≦ -15° C.). Thereaction mixture is stirred 15 minutes longer after which a solution of98.3 g. (0.575 mole) of benzyl bromide in 200 ml. ofN,N-dimethylformamide is added. The mixture is then warmed to roomtemperature and stirred 30 minutes longer. It is quenched by addition to6 liters of ice water. The quenched mixture is extracted six times with500 ml. of ether. The combined extract is washed twice with one literportions of water and once with one liter of saturated sodium chloride,dried over magnesium sulfate and evaporated to a quantitative yield ofthe title product.

PMR: α_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 0.8-2.0 (m,methylenes), 1.22 (s, gem dimethyl), 5.17 (s, benzylic methylene) and6.7-7.6 (two multiplets, ArH and PhH).

Ir: (chcl₃) 1592 and 1575 cm⁻¹.

Ms: m/e 390, 388 (M⁺), 375, 373, 354, 352, 305, 303 and 91.

And, 2-(3-benzyloxy-4-bromophenyl)-2-methylnonane is prepared in 95%(10.4 g.) yield from 2-(3-hydroxy-4-bromophenyl)-2-methylnonane (8.5 g.,0.027 mol.), sodium hydried (0.744 g., 0.031 mol.) and benzyl bromide(5.3 g., 0.031 mol.) as an oil.

PMR: α_(CDCl).sbsb.3^(TMS) 0.87 (terminal methyl), 1.23 (s,gemdimethyl), 5.18 (s, benzyl ether methylene), 6.8 (dd, J=8 and 2Hz, ArH),6.97 (d, J=2Hz, ArH) and 7.43 (m, ArH and PhH).

Ir: (chcl₃) 1600 and 1575 cm⁻¹.

Ms: m/e 404, 402 (M⁺), 305, 303, 91.

The compounds tabulated below are prepared according to the proceduresof Preparations C-F from appropriate reactants:

    ______________________________________                                         ##STR37##                                                                    Z                W                                                            ______________________________________                                        C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                             H                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                            H                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                             C.sub.6 H.sub.5                                              C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                             4-pyridyl                                                    C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                             2-pyridyl                                                    C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                            C.sub.6 H.sub.5                                              CH(CH.sub.3)(CH.sub.2).sub.2                                                                   C.sub.6 H.sub.5                                              CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                            4-ClC.sub.6 H.sub.4                                          CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                            4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.5 H                                                            (CH.sub.2).sub.11                                                                              H                                                            (CH.sub.2).sub.13                                                                              H                                                            (CH.sub.2).sub.4 C.sub.6 H.sub.5                                              (CH.sub.2).sub.8 H                                                            ______________________________________                                    

preparation g 3-benzyloxy-4-bromophenol

To a 0° C. slurry of 1.7 g. (42.5 mmoles) of potassium hydride in 35 ml.of N,N-dimethylformamide is slowly added a solution of 7.22 g. (38.2mmoles) of 4-bromoresorcinol. The resultant mixture is stirred for 30minutes and then 4.54 ml. (38.2 mmoles) of benzyl bromide is slowlyadded. The reaction mixture is stirred 3 hours longer at 0° C. and thenadded to 200 ml. of cold water and 200 ml. of ether. The ether extractis washed twice with 200 ml. portions of water, dried over magnesiumsulfate and evaporated to an oil. The crude oil is purified via columnchromatography on 400 g. of silica gel eluted with 25% ether-pentane toyield (in order of elution) 2.2 g. (16%) of 2,4-dibenzyloxybromobenzene,0.21 g. (2%) of 5-benzyloxy-2-bromophenol and 3.52 g. (33%) of3-benzyloxy-4-bromophenol.

5-Benzyloxy-2-bromophenol:

PMR: α_(CDCl).sbsb.3^(TMS) 4.98 (s, benzyl ether), 5.46 (bs, OH), 6.40(dd, J=8 and 2Hz, ArH), 6.60 (d, J=2Hz, ArH), 7.17 (d, J=8Hz, ArH) and7.33 (s, PhH).

Ir: (chcl₃) 3521, 3221, 1610 and 1600 cm⁻¹.

Ms: m/e 280, 278 (M⁺), 189, 187 and 91.

3-Benzyloxy-4-bromophenol:

PMR: α_(CDCl).sbsb.3^(TMS) 5.00 (s, benzyl ether methylene), 5.33 (bs,OH), 6.21 (dd, J=8 and 2Hz, ArH), 6.38 (d, J=2Hz, ArH) and 7.30 (m, ArHand PhH).

Ir: (chcl₃) 3546, 3257, 1603 and 1585 cm⁻¹.

Ms: m/e 280, 278 (M⁺) and 91.

PREPARATION H 2-Benzyloxy-4-[2-(5-phenylpentyloxy)]bromobenzene

A mixture of 3.50 g. (12.5 mmoles) of 3-benzyloxy-4-bromophenol, 3.48 g.(14.4 mmoles) of 2-(5-phenylpentyl)methanesulfonate and 5.17 g. (37.5mmoles) of anhydrous potassium carbonate in 20 ml. ofN,N-dimethylformamide is heated at 85° C. for 6 hours. It is then cooledand added to 200 ml. of water and 200 ml. of ether. The organic extractis washed twice with 150 ml. portions of water, dried over magnesiumsulfate and evaporated to an oil. The oil is purified via columnchromatography on 400 g. of silica gel eluted with 2:1 pentane:methylenechloride to yield 4.39 g. (82%) of the desired product as an oil.

PMR: α_(CDCl).sbsb.3^(TMS) 1.21 (d, J=6Hz, sidechain methyl), 1.7 (m,sidechain methylenes), 2.60 (m, sidechain benzyl methylene), 4.25 (m,sidechain methine), 5.00 (s, benzyl ether methylene), 6.22 (dd, J=8 and2Hz, C-5 ArH), 6.39 (d, J=2Hz, C-3 ArH) and 7.30 (m, PhH and C-6 ArH).

Ir: (chcl₃) 1587 cm⁻¹.

Ms: 426, 424 (m⁺), 280, 278 and 91.

The following compounds are similarly prepared from the appropriatemesylate CH₃ SO₃ --Z--W.

    ______________________________________                                         ##STR38##                                                                    (alk.sub.2)      W                                                            ______________________________________                                        (CH.sub.2).sub.4 4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.8 C.sub.6 H.sub.5                                              (CH.sub.2).sub.10                                                                              4-ClC.sub.6 H.sub.4                                          CH(CH.sub.3) (CH.sub.2).sub.8                                                                  C.sub.6 H.sub.5                                              CH(CH.sub.3)CH.sub.2                                                                           4-FC.sub.6 H.sub.4                                           C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                             C.sub.6 H.sub.5                                              CH.sub.2 CH(CH.sub.3)CH.sub.2                                                                  C.sub.6 H.sub.5                                              CH(CH.sub.3)(CH.sub.2).sub.10                                                                  H                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.5                                                             H                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                             H                                                            (CH.sub.2 ).sub.13                                                                             H                                                            (CH.sub.2).sub.13                                                                              C.sub.6 H.sub.5                                              CH(CH.sub.3)(CH.sub.2).sub.6                                                                   4-FC.sub.6 H.sub.4                                           C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                            4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.12                                                                              C.sub.6 H.sub.5                                              CH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                            4-ClC.sub.6 H.sub.4                                          C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                             H                                                            (CH.sub.2).sub.2 C(CH.sub.3 ).sub.2 (CH.sub.2).sub.2                                           H                                                            (CH.sub.2).sub.6 C.sub.6 H.sub.5                                              (CH.sub.2).sub.12                                                                              H                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                   4-pyridyl                                                    (CH.sub.2).sub.2 4-pyridyl                                                    CH(CH.sub.3)(CH.sub.2).sub.3                                                                   2-pyridyl                                                    (CH.sub.2).sub.5 3-pyridyl                                                    (CH.sub.2).sub.10                                                                              2-pyridyl                                                    CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                            4-pyridyl                                                    ______________________________________                                    

PREPARATION I 3-(3-Benzyloxy)benzyloxypropane

Sodium (0.2 mole) is dissolved in n-propylalcohol (1.0 mole) and thereaction mixture then cooled in an ice-bath. Then 0.2 mole of3-benzyloxybenzyl chloride is added with constant stirring over ahalf-hour period. The ice-bath is removed and the temperature graduallyraised to reflux. After 4 hours at reflux, the excess alcohol is removedby distillation under reduced pressure. The residue is treated withwater to dissolve the salt present and then extracted with diethylether. The extract is washed with water, dried (MgSO₄) and evaporated togive the title product.

In those instances where the alcohol reactant is not readily availableor is a solid at normal temperatures, a modification of this procedureis used. The appropriate alcohol is dissolved in acetone and heated withthe halide reactant in the presence of powdered potassium carbonate for6-8 hours. The reaction mixture is then cooled, water added and theether recovered as described above.

The following compounds are prepared in like manner from appropriatealcohols:

    ______________________________________                                         ##STR39##                                                                    (alk.sub.2) W        (alk.sub.2)    W                                         ______________________________________                                        (CH.sub.2).sub.2                                                                          H        --             C.sub.6 H.sub.5                           (CH.sub.2).sub.4                                                                          H        --             4-pyridyl                                 (CH.sub.2).sub.12                                                                         H        CH(CH.sub.3)(CH.sub.2).sub.2                                                                 C.sub.6 H.sub.5                           (CH.sub.2)  C.sub.6 H.sub.5                                                                        CH.sub.2       C.sub.6 H.sub.5                           CH(CH.sub.3)CH.sub.2                                                                      H        (CH.sub.2).sub.5                                                                             4-FC.sub.6 H.sub.4                        (CH.sub.2).sub.2 CH(CH.sub.3)                                                             C.sub.6 H.sub.5                                                                        CH.sub.2 CH(C.sub.2 H.sub.5)CH.sub.2                                                         H                                         ______________________________________                                    

bromination of the ethers according to the method of Preparation Eaffords the corresponding 2-bromo-5-(Z-W substituted)phenol benzylethers.

PREPARATION J 2-(3-Methoxyphenyl)-5-phenylpentane

A solution of 1-bromopropylbenzene (51.7 g.) in ether (234 ml.) is addeddropwise over a 2-hour period to a refluxing mixture of magnesium (7.32g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minuteslonger and then a solution of 3-methoxy-acetophenone (41.6 g.) in ether(78 ml.) is added dropwise and the mixture heated to reflux for 1.5hours. The reaction is quenched by addition of saturated ammoniumchloride (234 ml.), the ether layer is separated and the aqueous phaseextracted with ether (3 × 200 ml.). The combined ether extracts aredried over magnesium sulfate and concentrated under vacuum to yield anoil. The oil is hydrogenated in a mixture containing ethanol (300 ml.),concentrated hydrochloric acid (2 ml.) and 5% palladium-on-carbon (5g.). The catalyst is filtered off and the ethanol removed under vacuum.The residue is distilled under vacuum to give the title product.

PREPARATION K 2-(3-Hydroxyphenyl)-5-phenylpentane

A mixture of 2-(3-methoxyphenyl)-5-phenylpentane (18.4 g.) and pyridinehydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hourswith vigorous stirring. The reaction mixture is cooled, dissolved in 6Nhydrochloric acid (200 ml.) and diluted with water to 600 ml. Theaqueous solution is extracted with ethyl acetate (4 × 100 ml.), theethyl acetate extracts dried over sodium sulfate and concentrated undervacuum to yield the crude product. The product is purified by silica gelchromatography.

The following compounds are prepared from appropriate reactants by themethod of Preparation J and that of the above preparation:

    ______________________________________                                         ##STR40##                                                                    Z                W                                                            ______________________________________                                        CH(CH.sub.3)(CH.sub.2).sub.2                                                                   C.sub.6 H.sub.5                                              CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                            4-ClC.sub.6 H.sub.4                                          CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                            4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.5 H                                                            (CH.sub.2).sub.11                                                                              H                                                            (CH.sub.2).sub.13                                                                              H                                                            (CH.sub.2).sub.4 C.sub.6 H.sub.5                                              (CH.sub.2).sub.8 H                                                            ______________________________________                                    

bromination of the above compounds according to the procedure ofPreparation E affords the corresponding 4-bromo derivatives, e.g.2-(4-bromo-3-hydroxyphenyl)-5-phenylpentane.

PREPARATION L Ethyl 3-(3-Benzyloxyphenyl)crotonate (Wittig Reaction)

A mixture of 3-benzyloxyacetophenone (29.4 g., 0.13 mole) andcarbethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heatedunder a nitrogen atmosphere at 170° C. for 4 hours. The clear melt iscooled to room temperature, triturated with ether and the precipitate oftriphenyl phosphine oxide removed by filtration. The filtrate isconcentrated under vacuum to an oily residue which is chromatographedover silica gel (1500 g.) and eluted with benzene:hexane solutions ofincreasing benzene concentration beginning with 40:60 and ending with100% benzene. Concentration of appropriate fractions gives the productas an oily residue.

PREPARATION M 3-(3-Benzyloxyphenyl)butyl Tosylate

A solution of ethyl 3-(3-benzyloxyphenyl)crotonate (17.8 g., 60 mmole)in ether (250 ml.) is added to a mixture of lithium aluminum hydride(3.42 g., 90 mmole) and ether (250 ml.). Aluminum chloride (0.18 g.,1.35 mmole) is added and the mixture refluxed for 12 hours and thencooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6N) and water (10ml.) are then added successively to the reaction mixture. The inorganicsalts which precipitate are filtered off and the filtrate is thenconcentrated in vacuo to give the 3-(3-benzyloxyphenyl)butanol as anoil.

Tosyl chloride (11.1 g., 58.1 mmole) is added to a solution of3-(3-benzyloxyphenyl)-1-butanol (14.5 g., 57 mmole) in pyridine (90 ml.)at -45° C. The reaction mixture is held at -35° C. for 18 hours and isthen diluted with cold 2N hydrochloric acid (1500 ml.) and extractedwith ether (5 × 200 ml.). The combined extracts are washed withsaturated sodium chloride solution (4 × 250 ml.) and then dried (Na₂SO₄). Concentration of the dried extract affords the product as an oil.

PREPARATION N 3-(3-Benzyloxyphenyl)-1-phenoxybutane

A solution of phenol (4.56 g., 48.6 mmole) in dimethylformamide (40 ml.)is added under a nitrogen atmosphere to a suspension of sodium hydride(2.32 g., 48.6 mmole) of 50% previously washed with pentane) indimethylformamide (70 ml.) at 60° C. The reaction mixture is stirred forone hour at 60°-70° C., after which a solution of3-(3-benzyloxyphenyl)butyl tosylate (18.9 g., 46 mmole) indimethylformamide (80 ml.) is added. The reaction mixture is stirred at80° C. for a half hour and is then cooled to room temperature, dilutedwith cold water (2500 ml.) and extracted with ether (4 × 400 ml.). Thecombined extracts are washed successively with cold 2N hydrochloric acid(2 × 300 ml.) and saturated sodium chloride solution (3 × 300 ml.) andthen dried (Na₂ SO₄). Removal of the solvent under reduced pressureaffords the product as an oil. The oily residue is dissolved in benzeneand filtered through silica gel (100 g.). Concentration of the filtrateunder reduced pressure gives the product as an oil.

Repetition of Preparations L through N but using the 3-benzyloxyderivatives of benzaldehyde, acetophenone or propiophenone, theappropriate carbethoxy (or carbomethoxy) alkylidenetriphenylphosphorane,and the appropriate alcohol or phenol affords the following compounds.

    ______________________________________                                         ##STR41##                                                                    (alk.sub.1)   n      (alk.sub.2) W                                            ______________________________________                                        (CH.sub.2).sub.3                                                                            1      (CH.sub.2).sub.3                                                                          H                                            (CH.sub.2).sub.3                                                                            1      (CH.sub.2).sub.5                                                                          H                                            (CH.sub.2).sub.5                                                                            1      (CH.sub.2).sub.8                                                                          H                                            (CH.sub.2).sub.6                                                                            1      (CH.sub.2).sub.7                                                                          H                                            (CH.sub.2).sub.3                                                                            1      (CH.sub.2).sub.7                                                                          H                                            (CH.sub.2).sub.3                                                                            1      (CH.sub.2).sub.10                                                                         H                                            (CH.sub.2).sub.10                                                                           1      (CH.sub.2).sub.2                                                                          H                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                          1      (CH.sub.2).sub.4                                                                          H                                            (CH.sub.2).sub.4                                                                            1      CH.sub.2    C.sub.6 H.sub.5                              (CH.sub.2).sub.6                                                                            0      --          C.sub.6 H.sub.5                              (CH.sub.2).sub.13                                                                           0      --          H                                            (CH.sub.2).sub.6                                                                            0      --          H                                            (CH.sub.2).sub.6                                                                            1      CH.sub.2    4-ClC.sub.6 H.sub.4                          (CH.sub.2).sub.6                                                                            0      --          4-FC.sub.6 H.sub.4                           CH(CH.sub.3)(CH.sub.2).sub.2                                                                0      --          C.sub.6 H.sub.5                              CH(CH.sub.3)(CH.sub.2).sub.3                                                                0      --          C.sub.6 H.sub.5                              CH(CH.sub.3)(CH.sub.2).sub.6                                                                0      --          H                                            (CH.sub.2).sub.3                                                                            0      --          4-pyridyl                                    (CH.sub.2).sub.3                                                                            0      --          3-pyridyl                                    (CH.sub.2).sub.3                                                                            1      CH(CH.sub.3)                                                                              2-pyridyl                                    CH(CH.sub.3)(CH.sub.2).sub.2                                                                1      (CH.sub.2).sub.4                                                                          4-pyridyl                                    CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                         1      CH(CH.sub.3)                                                                              2-pyridyl                                    (CH.sub.2).sub.4                                                                            1      (CH.sub.2).sub.5                                                                          4-pyridyl                                    (CH.sub.2).sub.8                                                                            1      (CH.sub.2).sub.5                                                                          4-pyridyl                                    ______________________________________                                    

Bromination of the products according to the procedure of Preparation Eaffords the corresponding 2-bromo-5-[(alk₁)-O-(alk₂)_(n) -W]phenolbenzylethers.

PREPARATION O 4-(3-Hydroxyphenyl)-1-(4-pyridyl)pentane

A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide (17.5g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40ml.). The resulting mixture is then added dropwise to a slurry of 50%sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under anitrogen atmosphere at 0°-5° C. Following completion of addition, themixture is stirred for one hour at 0°-5° C. and then concentrated underreduced pressure. The concentrate is diluted with water (200 ml.) andthen acidified with 6N HCl. The aqueous acid solution is extracted withbenzene (4 × 50 ml.). It is then made basic and extracted with ethylacetate (3 × 50 ml.). Evaporation of the combined extracts after drying(MgSO₄) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.

Catalytic hydrogenation of the thus-produced pentene derivative inethanol at 45 p.s.i. in the presence of Pd/C (1 g. of 10%) andconcentrated HCl (1 ml.) affords the title product.

The pentane derivative thus obtained is demethylated by heating amixture of the compound (25 mmoles) and pyridine hydrochloride (35 g.)under a nitrogen atmosphere at 210° C. for 8 hours. The hot mixture ispoured into water (40 ml.) and the resulting solution made basic with 6Nsodium hydroxide. Water and pyridine are removed by distillation invacuo. Ethanol (50 ml.) is added to the residue and the inorganic saltswhich precipitate are filtered off. The filtrate is concentrated invacuo and the residue chromatographed on silica gel using as elutingagents 5% ethanol/benzene (4 liters), 10% ethanol/benzene (1 liter), 13%ethanol/benzene (1 liter) and 16% ethanol/benzene (5 liters). Theproduct is isolated by concentration of appropriate fractions of theeluate.

The 3-(3-methoxyphenyl)butyltriphenylphosphonium bromide is prepared byrefluxing a mixture of 1-bromo-3-(3-methoxyphenyl)butane (78.5 mmoles)and triphenyl phosphine (78.5 mmoles) in xylene (60 ml.) for 18 hours.The reaction mixture is then cooled to room temperature and filtered.The filter cake is washed with ether and the product dried in a vacuumdesiccator.

Repetition of this procedure but using the appropriatebromo-(3-methoxyphenyl)alkane and the appropriate aldehyde or ketoneaffords the following compounds.

    ______________________________________                                         ##STR42##                                                                    Z                W                                                            ______________________________________                                        (CH.sub.2).sub.3 2-pyridyl                                                    (CH.sub.2).sub.4 4-pyridyl                                                    CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                               3-pyridyl                                                    CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                               4-pyridyl                                                    CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                            4-pyridyl                                                    (CH.sub.2).sub.10                                                                              4-pyridyl                                                    ______________________________________                                    

Bromination of the above compounds according to the method ofPreparation E gives the corresponding 2-bromo-5-(Z-W)-phenols.

PREPARATION P 3-Methoxy-α-methylstyrene Oxide

To a solution of dimethylsulfoxonium methylide (69.4 mmoles) in dimethylsulfoxide (65 ml.) at room temperature is added solid3-dimethoxyacetophenone (8.33 g., 55.5 mmoles). The reaction mixture isstirred for one hour at 25° C., for one-half hour at 50° C. and is thencooled. The mixture is diluted with water (50 ml.) and added to amixture of ice water (200 ml.)-- ether (250 ml.)--low boiling petroleumether (25 ml.). The organic extract is washed twice with water (250ml.), dried (MgSO₄) and evaporated to an oil which is fractionallydistilled.

PREPARATION Q 2-(3-Methoxyphenyl)-2-hydroxypropyl-2-phenylethyl Ether

A mixture of dry 2-phenylethanol (30 ml., 251 mmoles) and sodium metal(690 mg., 30 mmoles) is heated at 110° C. for 30 minutes. The resulting1M solution of sodium 2-phenylethoxide is cooled to 60° C.,3-methoxy-α-methylstyrene oxide (1.69 g., 10.3 mmoles) added and thereaction heated 15 hours at 60° C. The reaction mixture is cooled andadded to a mixture of ether and water. The ether extract is dried overmagnesium sulfate and evaporated. Excess 2-phenylethanol is removed byvacuum distillation (b.p. ˜65° C., 0.1 mm.). The residue is purified viacolumn chromatography on silica gel 60 (300 g.) and eluted in 15 ml.fractions with 60% ether-pentane.

PREPARATION R 2-(3-Methoxyphenyl)propyl 2-Phenylethyl Ether

To a 0° C. solution of 2-(3-methoxyphenyl)-2-hydroxypropyl 2-phenylethylether (498 mg., 1.74 mmole) in pyridine (2 ml.) is added dropwisephosphorous oxychloride (477 ml., 5.22 mmole). The reaction is allowedto warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5hours at 20° C. and then added to ether (150 ml.) and 15% sodiumcarbonate (100 ml.). The organic phase is separated and washed with 15%sodium carbonate (3 × 50 ml.), dried over magnesium sulfate andevaporated to an oil. The oil is dissolved in absolute ethanol (15 ml.),10% palladium-on-carbon (100 mg.) added and the mixture stirred underone atmosphere of hydrogen gas. When hydrogen uptake ceases the reactionis filtered through diatomaceous earth and the filtrate evaporated to anoil. The oil is purified via preparation layer chromatography on silicagel plates, eluted twice with 6:1 pentane:ether to yield the titlecompound.

PREPARATION S 2-(3-Hydroxyphenyl)propyl 2-Phenylethyl Ether

A mixture of 2-(3-methoxyphenyl)propyl 2-phenylethyl ether (176 mg.,0.65 mmole), pyridine (0.4 ml., 4.96 mmole) and dry pyridinehydrochloride (4 g., 34.6 mmole) is heated at 190° C. for 6 hours. Thereaction mixture is cooled and added to a mixture of water (100 ml.) andether (150 ml.). The ether extract is washed once with water (50 ml.)and, along with a second ether extract (50 ml.) of the aqueous phase, isdried over magnesium sulfate and evaporated to an oil. The oil ispurified via preparative layer chromatography on silica gel plates,eluted six times with 30% ether-pentane to yield the title product.

The following compounds are prepared from appropriate alkanols by themethods of Procedures Q and R:

    ______________________________________                                         ##STR43##                                                                    (alk.sub.2)      W                                                            ______________________________________                                        (CH.sub.2).sub.7 H                                                            (CH.sub.2).sub.6 C.sub.6 H.sub.5                                              (CH.sub.2).sub.5 H                                                            CH(CH.sub.3)CH.sub.2                                                                           H                                                            CH(CH.sub.3)(CH.sub.2).sub.5                                                                   H                                                            (CH.sub.2)       4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.2 4-pyridyl                                                    (CH.sub.2).sub.2 4-ClC.sub.6 H.sub.4                                          (CH.sub.2).sub.2 CH(CH.sub.3)(CH.sub.2).sub.3                                                  H                                                            CH(CH.sub.3)CH.sub.2                                                                           H                                                            C(CH.sub.3).sub.2 CH.sub.2                                                                     H                                                            (CH.sub.2).sub.10                                                                              H                                                            CH.sub.2         C.sub.6 H.sub.5                                              ______________________________________                                    

preparation t 3-methoxy-β-methylstyrene Oxide

To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) intetrahydrofuran (one liter) is slowly added 3-methoxybenzaldehyde (1.0mole). The reaction mixture is stirred at -78° C. for 3 hours and thenallowed to warm to room temperature. It is then added to ether-water andthe ether phase separated. The ether phase is washed with water, dried(MgSO₄) and evaporated. Fractional distillation of the residue gives thetitle product.

PREPARATION U 3-(3-Hydroxyphenyl)-2-propylbutyl Ether

To a solution of sodium butoxide in butanol (0.5 liters of 1M) is added3-methoxy-β-methylstyrene oxide (6.33 mole). The mixture is heated for18 hours at 70° C. and is then cooled and added to a mixture ofether-water. The ether solution is separated, dried (MgSO₄) andevaporated to give the crude product2-(3-methoxyphenyl)-3-hydroxy-2-propylbutyl ether. It is purified bycolumn chromatography on silica gel with ether-pentane elution.

By means of the procedure of Preparation R the title product isproduced.

Similarly, the following are prepared from appropriate alcohols:

    ______________________________________                                         ##STR44##                                                                    (alk.sub.2)      W                                                            ______________________________________                                        (CH.sub.2).sub.2 H                                                            (CH.sub.2).sub.7 H                                                            (CH.sub.2).sub.3 C.sub.6 H.sub.5                                              (CH.sub.2).sub.2 4-FC.sub.6 H.sub.4                                           (CH.sub.2).sub.2 4-pyridyl                                                    CH(CH.sub.3)(CH.sub.2).sub.2                                                                   H                                                            CH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                            H                                                            CH(CH.sub.3)CH.sub.2                                                                           C.sub.6 H.sub.5                                              CH.sub.2         H                                                            (CH.sub.2).sub.2 4-ClC.sub.6 H.sub.4                                          ______________________________________                                    

preparation v 1-bromo-3-(3-methoxyphenyl)butane

A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (30.0 g.,0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reactionmixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed toroom temperature and stirred for an additional 30 minutes. The mixtureis poured over ice (200 g.) and the resulting mixture extracted withether (3 × 50 ml.). The combined extracts are washed with 5% sodiumhydroxide solution (3 × 50 ml.), saturated sodium chloride solution (1 ×50 ml.) and dried (Na₂ SO₄). Removal of the ether and vacuumdistillation of the residue affords the title product.

The following compounds are prepared from 3-methoxybenzaldehyde,3-methoxyacetophenone and 3-methoxypropiophenone and the appropriatecarbethoxyalkylidene triphenylphosphorane by the procedures ofPreparations L, M and the above procedure.

    ______________________________________                                         ##STR45##                                                                              Z                                                                   ______________________________________                                                  (CH.sub.2).sub.3                                                              (CH.sub.2).sub.4                                                              CH(C.sub.2 H.sub.5)CH.sub.2                                                   CH(CH.sub.3)CH.sub.2                                                          CH(CH.sub.3)(CH.sub.2).sub.3                                        ______________________________________                                    

preparation w 1-substituted-4-piperidones

A mixture of ethyl acrylate (3 moles) and the appropriate amine R₆ 'NH₂(1 mole) in dry ethanol (200 ml.) is stirred and refluxed for 48 hours.The reaction mixture is then fractionally distilled to give thecorresponding N-di-(2-carbethoxyethyl)-R₆ '-amine [R₆ '-N-(CH₂ -CH₂-COOC₂ H₅)₂ ].

The disubstituted amine (1 mole) is then cyclized by treatment withmetallic (bird shot) sodium (49.5 g.) in xylene (one liter) and themixture warmed to 50° C., care being taken to exclude moisture.Additional base is added drop-wise to maintain the reaction. Thereaction mixture is stirred at 50° C. for 3-4 hours following additionof the base and then cooled. Water (one liter) is cautiously added, theaqueous phase separated, extracted with ether (4 × 200 ml.) and thenacidified with concentrated hydrochloric acid. The acid solution issaturated with potassium carbonate and the oil which separates extractedwith ether. The ether solution is dried (K₂ CO₃) and evaporated. Theresidue is refluxed with 20% HCl (2 liters) for 3-4 hours and themixture then evaporated to dryness under reduced pressure to give thedesired 1-substituted-4-piperidone.

By means of this procedure (substantially that of Beckett, et al., J.Med. Pharm. Chem., 1, 37-58, 1959), the following compounds areprepared.

    ______________________________________                                         ##STR46##                                                                             R.sub.6 '                                                            ______________________________________                                                 C.sub.2 H.sub.5                                                               n-C.sub.3 H.sub.7                                                             i-C.sub.3 H.sub.7                                                             n-C.sub.4 H.sub.9                                                             sec-C.sub.4 H.sub.9                                                           t-C.sub.4 H.sub.9                                                             n-C.sub.5 H.sub.11                                                            n-C.sub.6 H.sub.13                                                            (CH.sub.2).sub.3 C.sub.6 H.sub.5                                              (CH.sub.2).sub.4 C.sub.6 H.sub.5                                              C.sub.3 H.sub.5                                                               furfuryl                                                                      tetrahydrofurfuryl                                                            tetrahydrothienylmethyl                                                       (CH.sub.2).sub.2 C.sub.6 H.sub.5                                              CH(CH.sub.3)C.sub.6 H.sub.5                                                   CH(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                 ______________________________________                                    

preparation x 1-r₆ '-substituted-Azacycloalkan-3-ones

A mixture of the appropriate N-(R₆ '-substituted)glycine ethyl ester andthe appropriate ω-halo ester BrCH₂ (CH₂)_(x) CH₂ COOC₂ H₅ (1 mole) isallowed to stand at room temperature for 24 hours. It is then dilutedwith ether, filtered and the ethereal solution evaporated.

The ω,ω'-dicarbethoxydialkyl-R₆ '-amines [H₅ C₂ OOC-CH₂ --NR₆ '--CH₂(CH₂)_(x) --CH₂ COOC₂ H₅ ] are then cyclized by heating a mixture ofequimolar amounts of the di-ester and sodium ethoxide at from 120°-130°C. under conditions which allow distillation of by-product ethanol. Whenremoval of alcohol is complete, water is added to the reaction mixtureand the resulting mixture extracted with ether. The aqueous solution isthen acidified with hydrochloric acid and refluxed until the solutiongives no color reaction with ferric chloride. Evaporation of thesolution affords the HCl salt of the 1-R₆ '-substituted-3-pyridone.Careful neutralization with potassium carbonate gives the free ketone.

In this manner the 1-R₆ '-substituted azacycloalkan-3-ones listed beloware prepared from appropriate N-R₆ '-glycine ethyl esters andappropriate ω-bromoalkanoic acid ethyl esters.

    ______________________________________                                         ##STR47##                                                                    x           R.sub.6 '                                                         ______________________________________                                        0          cyclohexylmethyl                                                   1          cyclopentylmethyl                                                  1          cyclohexylmethyl                                                   2          cyclobutylmethyl                                                   3          cyclohexylmethyl                                                   0          CH.sub.2 C.sub.6 H.sub.5                                           0          CH.sub.3                                                           0          n-C.sub.3 H.sub.7                                                  0          (CH.sub.2).sub.2 C.sub.6 H.sub.5                                   0          cyclobutylmethyl                                                   0          cyclopropylmethyl                                                  0          furfuryl                                                           0          2-tetrahydrothienylmethyl                                          1          CH.sub.3                                                           1          t-C.sub.4 H.sub.9                                                  1          i-C.sub.6 H.sub.13                                                 1          furfuryl                                                           1          tetrahydrofurfuryl                                                 1          2-tetrahydrothienylmethyl                                          1          (CH.sub.2).sub.2 C.sub.6 H.sub.5                                   1          (CH.sub.2).sub.4 C.sub.6 H.sub.5                                   1          cyclobutylmethyl                                                   1          cyclopropylmethyl                                                  2          CH.sub.3                                                           2          i-C.sub.3 H.sub.7                                                  2          n-C.sub.5 H.sub.11                                                 2          cyclopropylmethyl                                                  2          (CH.sub.2).sub.3 C.sub.6 H.sub.5                                   2          tetrahydrofurfuryl                                                 2          CH.sub.2 C.sub.6 H.sub.5                                           3          CH.sub.3                                                           3          sec-C.sub.4 H.sub.9                                                3          n-C.sub.6 H.sub.13                                                 3          (CH.sub.2).sub.3 C.sub.6 H.sub.5                                   3          cyclopropylmethyl                                                  3          2-2-tetrahydrothienylmethyl                                        3          CH.sub.2 C.sub.6 H.sub.5                                           1          n-C.sub.3 H.sub.7                                                  1          i-C.sub.3 H.sub.7                                                  0          2-thienylmethyl(thenyl)                                            1          2-thienylmethyl(thenyl)                                            0          CH(CH.sub.3)C.sub.6 H.sub.5                                        2          CH(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                               ______________________________________                                    

the N-R₆ '-glycine ethyl esters not described in the art are prepared byreacting 2 moles of the appropriate amine in anhydrous ether at 0°-10°C. with one mole of ethyl bromoacetate. The mixture is stirred for 3hours then allowed to stand overnight. The precipitate is filtered off,the ether evaporated and the residue vacuum distilled.

PREPARATION Y

Repetition of the procedure of Preparation X but using the appropriateN-(R₆ '-substituted)-β-alanine ethyl ester in place of the N-(R₆'-substituted)glycine ethyl ester affords compounds having the formula

    ______________________________________                                         ##STR48##                                                                    x           R.sub.6 '                                                         ______________________________________                                        2          CH.sub.3                                                           2          n-C.sub.6 H.sub.13                                                 2          (CH.sub.2).sub.3 C.sub.6 H.sub.5                                   2          cyclopropyl                                                        2          cyclopropylmethyl                                                  2          2-tetrahydrothienylmethyl                                          2          furfuryl                                                           3          C.sub.2 H.sub.5                                                    3          tetrahydrofurfuryl                                                 3          cyclopropyl                                                        3          (CH.sub.2).sub.4 C.sub.6 H.sub.5                                   ______________________________________                                    

preparation z 1-benzyl-4-(3-phenylpropyl)-3-piperidone

To a 0° C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide in7 ml. of tetrahydrofuran is slowly added a solution of 0.95 g. (5.0mmols.) of 1-benzyl-4-piperidone in 10 ml. of tetrahydrofuran. Theresultant mixture is stirred for one hour and is then added to 250 ml.of saturated ammonium chloride-250 ml. ether. The ether phase is driedover magnesium sulfate and evaporated. The residue is purified viacolumn chromatography on 200 g. of silica gel eluted with 50%ether-cyclohexane to yield 1-benzyl-4-(3-phenylpropyl)piperidinol.

The thus-prepared piperidinol (6.18 g., 20 mmols.) is then added to 2Nhydrochloric acid (250 ml.) and the mixture refluxed for 6 hours. It isthen evaporated under reduced pressure and the residue taken up in 500ml. of saturated sodium bicarbonate-300 ml. of ether-100 ml. ofdichloromethane. The organic phase is separated, dried (MgSO₄) andevaporated to an oil which is purified by column chromatography on 400g. of silica gel eluted with 50% ethercyclohexane to give the product1-benzyl-4-(3-phenylpropyl)-1,2,5,6-tetrahydropyridine.

Hydroboration and subsequent oxidation of the thus-produced1,2,5,6-tetrahydropyridine according to the procedure of Example 5 gives1-benzyl-4-(3-phenylpropyl)-3-piperidinol.

Oxidation of the 3-piperidinol compound by the procedure of Example 6yields the desired 1-benzyl-4-(3-phenylpropyl)-3-piperidone.

The following compounds are prepared in like manner from appropriateGrignard reagents R₂ 'MgBr and the appropriate 1-(R₆'-substituted)azacycloalkan-3-one:

    ______________________________________                                         ##STR49##                                                                    x        R.sub.6 '       R.sub.2 '                                            ______________________________________                                        1        CH.sub.3        CH.sub.3                                             1        CH.sub.3        n-C.sub.3 H.sub.7                                    1        CH.sub.3        n-C.sub.6 H.sub.13                                   1        n-C.sub.3 H.sub.7                                                                             n-C.sub.5 H.sub.11                                   1        i-C.sub.3 H.sub.7                                                                             C.sub.2 H.sub.5                                      1        t-C.sub.4 H.sub.9                                                                             n-C.sub.4 H.sub.9                                    1        i-C.sub.6 H.sub.13                                                                            CH.sub.3                                             1        THF             CH.sub.3                                             1        THF             n-C.sub.6 H.sub.13                                   1        CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3                                             1        CH.sub.2 C.sub.6 H.sub.5                                                                      n-C.sub.3 H.sub.7                                    1        (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              i-C.sub.3 H.sub.7                                    1        (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                              CH.sub.3                                             1        CH.sub.2 C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3 C.sub.6 H.sub.5                     1        C.sub.3 H.sub.5 CH.sub.3                                             1        C.sub.3 H.sub.5 n-C.sub.4 H.sub.9                                    1        C.sub.3 H.sub.5 CH.sub.2                                                                      CH.sub.3                                             1        C.sub.3 H.sub.5 CH.sub.2                                                                      n-C.sub.6 H.sub.13                                   1        C.sub.3 H.sub.5 CH.sub.2                                                                      (CH.sub.2).sub.2 C.sub.6 H.sub.5                     1        C.sub.3 H.sub.5 C.sub.6 H.sub.5                                      1        CH.sub.3        C.sub.6 H.sub.5                                      1        t-C.sub.4 H.sub.9                                                                             C.sub.6 H.sub.5                                      1        furfuryl        CH.sub.3                                             1        furfuryl        (CH.sub.2).sub.4 C.sub.6 H.sub.5                     1        furfuryl        n-C.sub.5 H.sub.11                                   1        THTM            CH.sub.3                                             1        THTM            sec-C.sub.4 H.sub.9                                  1        THTM            (CH.sub.2).sub.3 C.sub.6 H.sub.5                     1        THTM            (CH.sub.2).sub.4 C.sub.6 H.sub.5                     1        THF             C.sub.6 H.sub.5                                      0        CH.sub.3        CH.sub.3                                             0        CH.sub.3        i-C.sub.3 H.sub.7                                    0        n-C.sub.3 H.sub.7                                                                             i-C.sub.6 H.sub.13                                   0        CH.sub.3        C.sub.6 H.sub.5                                      0        n-C.sub.3 H.sub.7                                                                             (CH.sub.2).sub.3 C.sub.6 H.sub.5                     0        (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                              C.sub.2 H.sub.5                                      0        C.sub.3 H.sub.5 n-C.sub.3 H.sub.7                                    0        C.sub.3 H.sub.5 (CH.sub.2).sub.2 C.sub.6 H.sub.5                     0        C.sub.3 H.sub.5 CH.sub.2                                                                      CH.sub.3                                             0        furfuryl        C.sub.2 H.sub.5                                      0        THTM            CH.sub.3                                             0        THTM            C.sub. 6 H.sub.5                                     2        CH.sub.3        CH.sub.3                                             2        CH.sub.3        n-C.sub.5 H.sub.11                                   2        i-C.sub.3 H.sub.7                                                                             (CH.sub.2).sub.3 C.sub.6 H.sub.5                     2        n-C.sub.5 H.sub.11                                                                            CH.sub.3                                             2        CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3                                             2        CH.sub.2 C.sub.6 H.sub.5                                                                      n-C.sub.4 H.sub.9                                    2        i-C.sub.3 H.sub.7                                                                             (CH.sub.2).sub.3 C.sub.6 H.sub.5                     2        n-C.sub.5 H.sub.11                                                                            CH.sub.3                                             2        CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3                                             2        CH.sub.2 C.sub.6 H.sub.5                                                                      n-C.sub.4 H.sub.9                                    2        (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              CH.sub.3                                             2        C.sub.3 H.sub.5 C.sub.2 H.sub.5                                      2        C.sub.3 H.sub.5 (CH.sub.2).sub.3 C.sub.6 H.sub.5                     2        C.sub.3 H.sub.5 C.sub.6 H.sub.5                                      2        (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                              CH.sub.3                                             2        THF             CH.sub.3                                             2        THF             C.sub.6 H.sub.5                                      0        CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3                                             0        CH.sub.2 C.sub.6 H.sub.5                                                                      n-C.sub.6 H.sub.13                                   0        CH.sub.2 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                      3        CH.sub.3        CH.sub.3                                             3        CH.sub.3        i-C.sub.3 H.sub. 7                                   3        CH.sub.3        n-C.sub.6 H.sub.13                                   3        CH.sub.3        (CH.sub.2).sub.3 C.sub.6 H.sub.5                     3        sec-C.sub.4 H.sub.9                                                                           CH.sub.3                                             3        sec-C.sub.4 H.sub.9                                                                           C.sub.6 H.sub.5                                      3        sec-C.sub.4 H.sub.9                                                                           i-C.sub.3 H.sub.7                                    3        n-C.sub.6 H.sub.13                                                                            CH.sub.3                                             3        n-C.sub.6 H.sub.13                                                                            n-C.sub.5 H.sub.11                                   3        C.sub.3 H.sub.5 CH.sub.2                                                                      CH.sub.3                                             3        C.sub.3 H.sub.5 CH.sub.2                                                                      n-C.sub.4 H.sub.9                                    3        C.sub.3 H.sub.5 CH.sub.2                                                                      (CH.sub.2).sub.2 C.sub.6 H.sub.5                     3        C.sub.3 H.sub.5 CH.sub.2                                                                      C.sub.6 H.sub.5                                      3        THTM            C.sub.6 H.sub.5                                      3        THTM            (CH.sub.2).sub.3 C.sub.6 H.sub.5                     3        CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3                                             3        CH.sub.2 C.sub.6 H.sub.5                                                                      n-C.sub.4 H.sub.9                                    3        (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              CH.sub.3                                             3        THF             CH.sub.3                                             3        C.sub.3 H.sub.5 i-C.sub.3 H.sub.7                                    2        C.sub.3 H.sub.5 CH.sub.2                                                                      n-C.sub.3 H.sub.7                                    2        C.sub.3 H.sub.5 CH.sub.2                                                                      (CH.sub.2).sub.3 C.sub.6 H.sub.5                     2        n-C.sub.6 H.sub.13                                                                            CH.sub.3                                             ______________________________________                                    

what is claimed is:
 1. A compound having the formula ##STR50## whereineach of R₁ and R₆ is benzyl; Z is alkylene having from one to thirteencarbon atoms; W is hydrogen; and x is 1, and the pharmaceuticallyacceptable acid addition salts thereof.
 2. A compound according to claim1 wherein Z is alkylene having from 5 to 10 carbon atoms.
 3. Thecompound according to claim 2 wherein Z is --C(CH₃)₂ (CH₂)₆ --.